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Abstract:

Disclosed in certain embodiments is a method for relieving pain at a site
in a human or animal in need thereof, comprising administering by
injection or infiltration, a dose of a capsaicinoid and coadministering a
tricyclic antidepressant.

Claims:

1. A method for relieving pain at a site in a human or animal in need
thereof, comprising: administering at a discrete painful site in a human
or animal in need thereof a single injectable or implantable dose of a
capsaicinoid in an amount effective to denervate said discrete site
without eliciting an effect outside the discrete location and to
attenuate pain emanating from said site, said effective dose being from
about 1 mcg to about 5000 mcg of capsaicin or a therapeutically
equivalent dose of a capsaicinoid other than capsaicin; and
coadministering an amount of a tricyclic antidepressant.

2. The method of claim 1, wherein the tricyclic antidepressant is in the
same formulation as the capsaicinoid.

3. The method of claim 1, wherein the tricyclic antidepressant is in a
different formulation than the capsaicinoid.

4. The method of claim 1, wherein the tricyclic antidepressant is
administered by a different route than the capsaicinoid.

5. The method of claim 1, wherein the tricyclic antidepressant is
administered by the same route as the capsaicinoid.

10. The method of claim 8, wherein the tricyclic antidepressant is
administered orally.

11. The method of claim 8, wherein the tricyclic antidepressant is
administered parenterally.

12. The method of claim 1, wherein the tricyclic antidepressant is in an
effective amount to provide an antinociceptive effect.

13. The method of claim 1, further comprising administering a local
anesthetic to the human or animal.

14. The method of claim 1, wherein said dose of capsaicin is from about 10
to about 3000 mcg.

15. The method of claim 1, wherein said dose of capsaicin is from about
300 to about 1200 mcg.

16. The method of claim 1, wherein said dose of capsaicinoid is
administered in a pharmaceutically acceptable vehicle for injection or
implantation.

17. The method of claim 16, wherein said pharmaceutically acceptable
vehicle is an aqueous vehicle is selected from the group consisting of
Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose
Injection, Sterile Water Injection, Dextrose, Lactated Ringers Injection
and any combinations or mixtures thereof.

18-20. (canceled)

21. A method for attenuating pain at a surgical site or an open wound in a
human or animal, comprising: infiltrating a dose of a capsaicinoid in an
amount effective to denervate a site selected from a surgical site or an
open wound without eliciting an effect outside the site, said effective
dose being from about 1 mcg to about 15,000 mcg of capsaicin or a
therapeutically equivalent dose of a capsaicinoid other than capsaicin;
and coadministering an amount of a tricyclic antidepressant.

22. The method of claim 21, wherein the tricyclic antidepressant is in the
same formulation as the capsaicinoid.

23. The method of claim 21, wherein the tricyclic antidepressant is in a
different formulation than the capsaicinoid.

[0002]This application is directed to compositions and methods for
relieving pain at a specific site, for example, associated with
inflammation of joints, tendons, nerves, muscle, and other soft tissues,
nerve injury and neuropathies, and pain from tumors in soft tissues or
bone.

BACKGROUND OF THE INVENTION

[0003]Capsaicin, a pungent substance derived from the plants of the
solanaceae family (hot chili peppers) has long been used as an
experimental tool because of its selective action on the small diameter
afferent nerve fibers C-fibers and A-delta fibers that are believed to
signal pain. From studies in animals, capsaicin appears to trigger
C-fiber membrane depolarization by opening cation channels permeable to
calcium and sodium. Recently one of the receptors for capsaicin effects
has been cloned. Capsaicin can be readily obtained by ethanol extraction
of the fruit of capsicum frutescens or capsicum annum. Capsaicin is known
by the chemical name
N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide. Capsaicin is
practically insoluble in water, but freely soluble in alcohol, ether,
benzene and chloroform. Therapeutically capsaicin has been used as a
topical analgesic. Capsaicin is available commercially as Capsaicin USP
from Steve Weiss & Co., 315 East 68th Street, New York, N.Y. 10021
and can also be prepared synthetically by published methods. See
Michalska et al., "Synthesis and Local Anesthetic Properties of
N-substituted 3,4-Dimethoxyphenethylamine Derivatives", Diss Pharm.
Pharmacol., Vol. 24, (1972), pp. 17-25, (Chem. Abs. 77: 19271a),
discloses N-pentyl and N-hexyl 3,4-dimethoxyphenylacetamides which are
reduced to the respective secondary amines.

[0004]Capsaicin is listed in the pharmacopoeias of the United Kingdom,
Australia, Belgium, Egypt, Germany, Hungary, Italy, Japan, Poland,
Portugal, Spain, and Switzerland and has previously been listed in the
United States Pharmacopoeia and the National Formulary. The FDA proposed
monographs on analgesic drug products for over-the-counter (OTC) human
use. These include capsaicin and capsicum preparations that are regarded
as safe and effective for use as OTC external analgesics. Capsaicin is
the only chemical entity of Capsicum recognized by the FDA. Capsaicin
(USP) contains not less than 110% total capsaicinoids which typically
corresponds to 63% pure capsaicin. USP capsaicin is trans-capsaicin
(55-60%) and also contains the precursors dihydrocapsaicin and
nordihydrocapsaicin.

[0005]Capsaicin mediated effects include: (i) activation of nociceptors in
peripheral tissues; (ii) eventual desensitization of peripheral
nociceptors to one or more stimulus modalities; (iii) cellular
degeneration of sensitive A-delta and C-fiber afferents; (iv) activation
of neuronal proteases; (v) blockage of axonal transport; and (vi) the
decrease of the absolute number of nociceptive fibers without affecting
the number of non-nociceptive fibers.

[0006]The dosage forms of capsaicin which have been most widely studied
clinically are capsaicin containing creams (Zostrix, Zostrix-HP, and
Axsain). These products have been examined in a broad spectrum of painful
conditions including osteoarthritis. However the efficacy of topically
administered capsaicin in arthritis in general has proven to be limited.

[0008]Humans have long been exposed to dietary sources of
capsaicin-containing spices and to topical preparations used for a
variety of medical indications. This vast experience has not revealed
significant or lasting adverse effects of capsaicin exposure. The recent
determination of capsaicin's potential therapeutic effects on
unmyelinated sensory afferent nerve fibers require diligent consideration
of this compound for further pharmaceutical development.

[0009]Because of capsaicin's ability to desensitize nociceptors in
peripheral tissues, its potential analgesic effects have also been
assessed in various clinical trials. However, since the application of
capsaicin itself frequently causes burning pain and hyperalgesia apart
from the neuropathic pain being treated, patient compliance has been poor
and the drop out rates during clinical trials have exceeded fifty
percent. The spontaneous burning pain and hyperalgesia are believed to be
due to intense activation and temporary sensitization of the peripheral
nociceptors at the site of capsaicin application. This activation and
sensitization occur prior to the desensitization phase. The activation
phase could be a barrier to use of capsaicin because of the pain
produced.

[0010]It would therefore be advantageous to provide methods and
compositions including capsaicin or capsaicin analogues thereof with
effective concentrations to cause an analgesic effect without the side
effects normally associated with the use of capsaicin.

OBJECTS AND SUMMARY OF THE INVENTION

[0011]It is an object of the present invention to provide compositions and
methods for providing pain relief in humans and animals by administering
an injectable or implantable dose of capsaicin or capsaicin analogue to a
site for the treatment of acute or chronic pain, nociceptive and
neuropathic pain, pre- and post-operative pain, cancer pain, pain
associated with neurotransmitter dysregulation syndromes and orthopedic
disorders.

[0012]It is another object of the invention to provide compositions and
methods for attenuating pain at a discrete site in a human or animal via
the administration of a capsaicinoid via injection or implantation at the
discrete site.

[0013]It is another object of the present invention to provide
compositions and methods for relieving pain at an intra-articular site or
at a body space by administering an injectable or implantable single dose
of capsaicin or capsaicin analogue to the intra-articular site or body
space.

[0014]It is an object of the present invention to provide compositions and
methods for providing pain relief in humans and animals by administering
via infiltration a dose of capsaicin or capsaicin analogue to a surgical
site or open wound for the treatment of acute or chronic pain,
nociceptive and neuropathic pain, pre- and post-operative pain, cancer
pain, pain associated with neurotransmitter dysregulation syndromes and
orthopedic disorders.

[0015]It is another object of the present invention to provide
compositions and methods for attenuating pain at a surgical site in a
human or animal via the administration of a capsaicinoid via infiltration
at the surgical site.

[0016]It is another object of the present invention to provide
compositions and methods for attenuating pain at an open wound in a human
or animal via the administration of a capsaicinoid via infiltration at
the open wound.

[0017]It is a further object of the invention to provide compositions and
methods for treatment of sports-related injuries utilizing injectable or
implantable capsaicinoids.

[0018]It is a further object of the invention to provide compositions and
methods for treatment of pain associated with median sternotomy utilizing
infiltratable capsaicinoids.

[0019]It is a further object of the invention to provide compositions and
methods for treatment of pain associated with mastectomy utilizing
infiltratable capsaicinoids.

[0020]It is a further object of the invention to provide compositions and
methods for treatment of pain associated with orthopedic surgical
procedures utilizing infiltratable capsaicinoids.

[0021]It is a further object of the invention to provide compositions and
methods for treatment of orthopedic disorders or injuries utilizing
injectable or implantable capsaicinoids.

[0022]It is a further object of the invention to provide compositions and
methods for treating acute traumatic pain utilizing injectable,
implantable or infiltratable capsaicinoids.

[0023]It is a further object of the invention to provide compositions and
methods for treating neuropathic pain utilizing injectable, implantable
or infiltratable capsaicinoids.

[0024]It is a further object of the invention to provide compositions and
methods for treating nociceptive pain utilizing injectable, implantable
or infiltratable capsaicinoids.

[0025]It is a further object of the invention to provide compositions and
methods for treating neurotransmitter-dysregulation syndromes utilizing
injectable, implantable or infiltratable capsaicinoids.

[0026]In accordance with the above objects and others, the invention is
directed in part to a method for attenuating or relieving pain at a site
in a human or animal in need thereof, comprising administering via
injection, implantation or infiltration at a discrete site, a surgical
site, or an open wound in a human or animal in need thereof a single dose
of capsaicin in an amount effective to denervate the discrete site
without eliciting an effect outside the discrete location and to
attenuate pain emanating from said site, the dose ranging from about 1
μg to about 5,000 μg capsaicin or a therapeutically equivalent dose
of a capsaicinoid other than capsaicin when said dose is injected or
infiltrated into a discrete site in the human or animal, and the dose
ranging from about 1 μg to about 15,000 μg capsaicin or a
therapeutically equivalent dose of a capsaicinoid other than capsaicin
when said dose is infiltrated into a surgical site or an open wound. In
other words, the term "capsaicinoid" is meant to encompass formulations
where the drug is capsaicin, a capsaicinoid other than capsaicin, or a
mixture of capsaicin with one or more other capsaicinoids (the total
amount of all capsaicinoid drug being based on a therapeutically
equivalent dose to dose from about 1 μg to about 5,000 μg capsaicin
for injection or infiltration, and the total amount of all capsaicinoid
drug being based on a therapeutically equivalent dose to dose from about
1 μg to about 15,000 μg capsaicin for infiltration).

[0027]The present invention is further directed in part to a method for
attenuating or relieving pain at a site in a human or animal in need
thereof, comprising administering at a discrete painful site in a human
or animal in need thereof a single injectable or implantable dose of a
capsaicinoid in an amount effective to denervate said discrete site
without eliciting an effect outside the discrete location and to
attenuate pain emanating from said site, said effective dose being from
about 1 μg to about 5,000 μg of capsaicin or a therapeutically
equivalent dose of a capsaicinoid other than capsaicin. In certain
preferred embodiments, the dose of capsaicin for injection or
implantation is from about 10 to about 3000 μg, and preferably from
about 300 to about 1200 μg. In preferred embodiments, the dose of
capsaicinoid is administered in a pharmaceutically and physiologically
acceptable vehicle for injection or implantation, which may optionally
further include one or more pharmaceutical excipient. In certain
preferred embodiments, a local anesthetic may be administered prior to or
concurrently with said dose of capsaicinoid in an amount and location
effective to attenuate an initial hyperalgesic effect of the administered
dose of capsaicinoid. The local anesthetic may be administered, e.g., by
direct injection into the site where said dose of capsaicinoid is
administered, or as a proximal, regional, somatic, or neuraxial block.
General anesthesia may be used, if necessary. The dose of capsaicinoid
may be injected or implanted subcutaneously, intramuscularly,
itrathecally, epidurally, intraperitoneally, caudally intradermally or
intracutaneously, intercostally at a single nerve, intra-articularly,
intrasynovially, intraspinally, intra-arterially or into body spaces.
Intra-articular administration of the formulations of the invention may
be, e.g., into a joint selected from the group consisting of knee, elbow,
hip, sternoclavicular, temporomandibular, carpal, tarsal, wrist, ankle,
intervertebral disk, ligamentum flavum and any other joint subject to
pain.

[0028]In certain other embodiments of the present invention, there is
provided a method for attenuating or relieving pain at a surgical site or
open wound in a human or animal in need thereof, comprising administering
via infiltration at a surgical site or open wound in a human or animal in
need thereof a single dose of capsaicin in an amount effective to
denervate the surgical site or open wound without eliciting an effect
outside the surgical site or open wound, the dose ranging from about 1
μg to about 15,000 μg. In certain preferred embodiments, the
effective dose of capsaicinoid is from about 500 to about 15,000 μg
capsaicin, or from about 600 to about 10,000 μg capsaicin, or a
therapeutically equivalent dose of a capsaicinoid other than capsaicin.
In certain preferred embodiments, the dose of capsaicinoid is
administered in a pharmaceutically acceptable vehicle for infiltration in
a volume from about 0.1 to about 1000 ml. In certain preferred
embodiments, the dose of capsaicinoid is administered in a
pharmaceutically acceptable vehicle for infiltration in a volume from
about 1 ml to about 100 ml. In other further preferred embodiments, the
dose of capsaicinoid is administered in a pharmaceutically acceptable
vehicle for infiltration in a volume from about 5 ml to about 30 ml. In
certain preferred embodiments where the capsaicinoid is infiltrated into
a surgical site or an open wound, the method further comprises
administering a local or general anesthetic prior to or concurrently with
said dose of capsaicinoid. The dose of local anesthetic may be, e.g., an
amount and location effective to attenuate an initial hyperalgesic effect
of said administered dose of capsaicinoid. The local anesthetic may be
administered by infiltration to the surgical or wound site. In certain
preferred embodiments, the administration of capsaicinoid at the site
provides attenuation of pain in proximity to the surgical or wound site
for at least about 48 hours, and preferably for at least about one week.

[0029]The present invention is further directed in part to a method for
attenuating or relieving pain at a surgical site or open wound in a human
or animal in need thereof, comprising administering at a surgical site or
open wound in a human or animal in need thereof a single infiltratable
dose of a capsaicinoid in an amount effective to denervate said surgical
site or open wound without eliciting an effect outside the surgical site
or open wound, said effective dose being from about 1 μg to about
15,000 μg of capsaicin or a therapeutically equivalent dose of a
capsaicinoid other than capsaicin.

[0030]The dose of capsacinoid administered by infiltration into the
surgical site or open wound may be administered directly onto the tissue,
muscle or bone. In other embodiments, the dose of capsaicinoid may be
administered intra-articularly intra-sternally, intrasynovially,
intra-bursally or into body spaces. Intra-articular administration of the
formulations of the invention may be, e.g., into a joint selected from
the group consisting of knee, elbow, hip, sternoclavicular,
temporomandibular, carpal, tarsal, wrist, ankle, intervertebral disk,
ligamentum flavum and any other joint subject to pain.

[0031]The invention is further directed in part to a method of treating
acute traumatic pain associated with an injury, comprising injecting a
capsaicinoid in a physiologically compatible vehicle through the skin of
a patient in proximity to an injury, said dose of capsaicinoid being
sufficient to attenuate the dull, aching pain associated with C-fibers in
proximity to the injury and such that the patient continues to have
sensation in proximity to the injury and without affecting sharp
protective pain associated with A-delta fibers in proximity to the site,
the dose of capsaicinoid being therapeutically equivalent to a dose of
capsaicin in an amount from about 300 to about 1500 μg and being
effective to attenuate dull, aching pain in proximity to the injury for
at least about 48 hours.

[0032]The invention is further directed in part to a method of treating
acute traumatic pain associated with surgery or open wound injury,
comprising administering via infiltration a capsaicinoid in a
physiologically compatible vehicle at the surgical site or open wound of
a patient, said dose of capsaicinoid being sufficient to attenuate the
dull, aching pain associated with C-fibers in proximity to the surgical
site or open wound and such that the patient continues to have sensation
in proximity to the surgical site open wound and without affecting sharp
protective pain associated with A-delta fibers in proximity to the
surgical site or open wound, the dose of capsaicinoid being
therapeutically equivalent to a dose of capsaicin in an amount from about
600 to about 15,000 μg and being effective to attenuate dull, aching
pain in proximity to the surgical site or open wound for at least about
48 hours.

[0033]In certain preferred embodiments, the capsaicinoid is capsaicin
itself. In more preferred embodiments, the capsaicinoid comprises
trans-capsaicin. In most preferred embodiments, the capsaicinoid is at
least about 97% trans-capsaicin.

[0034]The single injectable, implantable or infiltratable dose of a
capsaicinoid administered at a discrete site, surgical site or open wound
in accordance with the present invention is preferably in an amount
effective to a) produce a selective, highly-localized destruction or
incapacitation of C-fibers and/or A-delta fibers in a discrete, localized
area responsible for the initiation of pain for the purpose of reducing
or eliminating pain arising from a discrete locus, and b) minimize
potential adverse consequences of C-fiber and/or A-delta activation and
or damage outside of the locus of pain.

[0035]The present invention is also directed to an injectable or
implantable pharmaceutical composition for attenuating pain at a site in
a human or animal in need thereof, consisting essentially of from 1 μg
to 5000 μg of a capsaicinoid comprising trans-capsaicin and a
pharmaceutically acceptable vehicle for injection or implantation. In
certain preferred embodiments, the dose of trans-capsaicin ranges from
about 10 μg to about 3000 μg, from about 300 μg to about 1500
μg, or preferably from about 400 μg to about 1200 μg.

[0036]The present invention is also directed to an infiltratable
pharmaceutical composition for attenuating pain at a surgical site or
open wound in a human or animal in need thereof, consisting essentially
of from 1 μg to 15,000 μg of a capsaicinoid comprising
trans-capsaicin and a pharmaceutically acceptable vehicle for
infiltration. In certain preferred embodiments, the dose of
trans-capsaicin ranges from about 600 μg to about 15,000 μg, from
about 600 μg to about 10,000 μg, or preferably from about 1,000
μg to about 10,000 μg.

[0037]In order that the invention described herein may be more fully
understood, the following definitions are provided for the purposes of
this disclosure:

[0038]The term "injection" shall mean administration of capsaicin to a
discrete site through the skin of a human or animal.

[0039]The term "implantation" shall mean administration of capsaicin to a
discrete site by embedding the dose of capsaicin into the skin, tissue,
muscles, tendons, joints, or other body parts of a human or animal.

[0040]The term "infiltration" or "infiltratable" shall mean administration
into a discrete surgical site or open wound in a human or animal.

[0041]As used herein, the term "capsaicinoid" means capsaicin, capsaicin
USP and purified capsaicin, capsaicin analogues and derivatives thereof
(collectively referred to as capsaicinoids in this specification and
appended claims) that act at the same pharmacologic sites, e.g., VR1, as
capsaicin, unless otherwise specified.

[0042]Acute pain shall mean any pain that presents with a rapid onset
followed by a short, severe course, e.g., headache, pain associated with
cancer, fractures, strains, sprains, and dislocations of bones, joints,
ligaments and tendons.

[0043]Chronic pain shall mean pain that lasts for a long period of time or
is marked by frequent recurrence, e.g., pain associated with terminal
illnesses, arthritis, autoimmune diseases; or neuropathic pain caused by
degenerative diseases such as diabetes mellitus or spinal degeneration,
or resulting from neural remodeling following traumatic injury or
surgery.

[0044]As used herein, the term "local anesthetic" means any drug or
mixture of drugs that provides local numbness and/or analgesia.

[0045]By co-administration it is meant either the administration of a
single composition containing both the capsaicin and an additional
therapeutically effective agent(s), e.g., local anesthetic or phenol, or
the administration of a capsaicin and the additional therapeutically
effective agent(s) as separate compositions within short enough time
periods that the effective result is equivalent to that obtained when
both compounds are administered as a single composition.

BRIEF DESCRIPTION OF THE DRAWINGS

[0046]The following drawings are illustrative of embodiments of the
invention and are not meant to limit the scope of the invention as
encompassed by the claims.

[0047]FIG. 1 is a graph displaying the plasma concentration of the 10
μg, 100 μg and 300 μg doses of capsaicin administered to study
subjects entered into the Osteoarthritis Safety Study exemplified in
Example 1.

[0048]FIG. 2 is a graph displaying the percent reduction in VAS score
compared to baseline in study subjects entered into the Osteoarthritis
Safety Study exemplified in Example 1.

[0049]FIG. 3 is a graph displaying the NRS Pain Score in study subjects
entered into the Osteoarthritis Efficacy Study exemplified in Example 2.

[0050]FIG. 4 is a graph displaying a comparison of VAS Pain Score between
subjects entered into the Bunionectomy Efficacy study exemplified in
Example 3.

[0051]FIG. 5 is a graph displaying a comparison of the percent of subjects
entered in to the Bunionectomy Efficacy study exemplified in Example 3
requiring rescue medication.

DETAILED DESCRIPTION OF THE INVENTION

[0052]The compositions and methods disclosed herein can be used for
treating pain at a specific site with an effective amount of capsaicin or
capsaicin analogue, hereinafter collectively referred to as
"capsaicinoids". In one preferred embodiment, the methods involve
administration of an effective amount of capsaicinoid to a site in a
human or animal for relieving pain at the site.

[0053]In another embodiment, the methods involve providing anesthesia to
the site where the capsaicinoid is to be administered, and then
administering an effective amount of capsaicinoid to the site. The
anesthesia can be provided directly to the site, or at a remote site that
causes anesthesia at the site where the capsaicinoid is to be
administered. For example, epidural regional anesthesia can be provided
to patients to which the capsaicinoid is to be administered at a site
located from the waist down. Alternatively, a local anesthetic may be
administered as a regional block, a proximal block, a somatic block, or a
neuraxial block. The anesthetic may be administered as a general
anesthetic, as a spinal block, as an epidural block, or as a nerve block.
Preferably, in the embodiments in which a local anesthetic is
administered, the local anesthetic is administered prior to
administration of the capsaicinoid, such that the local anesthetic has
provided temporary anesthesia to the area to be treated with the
capsaicinoid.

[0054]Examples of local anesthetic agents which can be used include
bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine,
prilocalne, mepivacaine, etidocaine, tetracaine, lidocaine, and
xylocaine, and mixtures thereof and any other art-known pharmaceutically
acceptable local anesthetic. The local anesthetic can be in the form of a
salt, for example, the hydrochloride, bromide, acetate, citrate,
carbonate or sulfate. More preferably, the local anesthetic agent is in
the form of a free base. Preferred local anesthetic agents include, e.g.,
bupivacaine. For bupivacaine, the free base provides a slower initial
release and avoids an early "dumping" of the local anesthetic at the
infiltration site. Other local anesthetics may act differently. Local
anesthetic agents typically administered systematically may also be used
in those cases where the means of administration results only in a local
effect, rather than systemic.

[0055]The dose of local anesthetic will depend on the anesthetic being
administered as well as the site where the local anesthetic is
administered. For example, in embodiments where the local anesthetic is
administered via a regional block (e.g., an ankle block), the dose of
anesthetic ranges from about 1 ml up to about 30 ml of a 0.5% solution
(e.g., bupivacaine). In other embodiments a 3 mg/kg dose (maximum 200 mg)
of a 2% solution (e.g., lidocaine) can be administered by intra-articular
infiltration. In other embodiments the dose of local anesthetic can range
between 0.5 ml to about 60 ml of a 0.25% to 5% solution.

[0056]Alternatively, phenol can be administered at the surgical site or
open wound to be treated in place of (or in addition to) a local
anesthetic to anesthesize the area. Phenol can preferably be administered
prior to administration of the capsaicinoid, or can be co-administered
with the dose of capsaicinoid. By co-administration it is meant either
the administration of a single composition containing both the
capsaicinoid and the phenol, or the administration of the capsaicinoid
and the phenol as separate compositions within short enough time periods
that the effective result is equivalent to that obtained when both
compounds are administered as a single composition.

[0057]Prior to the present invention, for example, in U.S. Pat. No.
4,313,958 (LaHann), capsaicin is described as producing analgesia when
administered via "systemic administration" (i.e., intrathecal, epidural,
intramuscular, intravenous, intraperitoneal and subcutaneous). Animal
testing was accomplished via "stair-step dosing" which purportedly was
said to reduce or eliminate some of the side affects of capsaicin. It is
reported therein that capsaicin, when systemically delivered in final
doses of 25 mg/kg or less prior to ultra violet radiation, prevented
radiation induced hyperalgesia, but did not elevate the pain threshold
above normal range. Only when larger doses of capsaicin were administered
systemically, i.e. final doses of capsaicin being 50 mg/kg or greater,
was the pain threshold elevated. LaHann hypothesized (but did not
exemplify), that for clinical use in humans, total doses from 0.05 mg/kg
to 1,000 mg/kg were acceptable and total doses from 0.25 mg/kg to 500
mg/kg were preferred. The rats weighed between 125 and 175 grams and the
total administered dose of capsaicin ranged from 27 mg/kg to 102 mg/kg
(or a total dose injected subcutaneously of about 3.375 mg to about 17.85
mg capsaicin).

[0058]More recently, U.S. Pat. No. 5,962,532 (Campbell et al) describes an
injection volume of 0.1 to 20 ml and a concentration of capsaicin between
0.01 to 10% for parenteral administration, which calculates to a total
dose of capsaicin of between 0.01 mg to 2,000 mg, based on volume and
concentration.

[0059]In contrast, in the present invention, the administration of
microgram quantities of capsaicin into discrete localized areas, surgical
sites or open wounds responsible for the treatment and/or attenuation of
pain recognizes significant advantages over system-wide exposure to
milligram quantities in order to produce a therapeutic effect through
alteration of sensory nerve function in a limited area.

[0060]In the present invention, a single dose from about 1 μg to 5,000
μg of capsaicin, or a therapeutically equivalent dose of one or more
other capsaicinoids, is administered via injection or implantation to
produce a selective, highly-localized destruction or incapacitation of
C-fiber and/or A-delta-fiber in discrete localized areas responsible for
the initiation of pain for the purpose of eliminating pain arising from
that locus, while minimizing potential adverse consequences of C-fiber
and/or A-delta-fiber activation and/or damage outside of the locus of
pain. In certain preferred embodiments, from about 10 to about 3000
micrograms of capsaicin, or a therapeutically equivalent dose of one or
more other capsaicinoids, is administered at the site. In certain
preferred embodiments, the amount of capsaicin administered at the site
is preferably from about 100 to about 1000 micrograms. In certain other
embodiments the amount of capsaicin administered at the site is
preferably from about 10 to about 1000 micrograms, more preferably from
20 to about 300 micrograms, and most preferably from about 35 to about
200 micrograms. In other words, the present invention is directed to
administration of a single dose of capsaicin or other capsaicinoid(s) by
injection or implantation in an amount that is greatly reduced as
compared to the dosage range previously considered useful by those
skilled in the art to denervate the nerve fibers in a discrete, localized
area without eliciting a systemic effect (e.g., an effect beyond that
discrete, localized location).

[0061]In other embodiments of the present invention, a single dose of from
about 1 μg to 15,000 μg of capsaicin, or a therapeutically
equivalent dose of one or more other capsaicinoids, is administered via
infiltration to produce a selective, highly-localized destruction or
incapacitation of C-fiber and/or A-delta-fiber in discrete localized
areas responsible for the initiation of pain for the purpose of
eliminating pain arising from that locus, while minimizing potential
adverse consequences of C-fiber and/or A-delta-fiber activation and/or
damage outside of the locus of pain. In certain preferred embodiments,
from about 600 to about 15,000 micrograms of capsaicin, or a
therapeutically equivalent dose of one or more other capsaicinoids, is
administered at the surgical site or open wound. In certain preferred
embodiments, the amount of capsaicin and/or preferably the range of
capsaicin administered at the surgical site or open wound is from about
1,000 to about 10,000 micrograms. In other words, the present invention
is directed to administration of a single dose of capsaicin or other
capsaicinoid(s) by infiltration in an amount that is greatly reduced as
compared to the dosage range previously considered useful by those
skilled in the art to denervate the nerve fibers in a discrete, localized
area without eliciting a systemic effect (e.g., an effect beyond that
discrete, localized location).

[0062]Capsaicinoids (capsaicin analogues) with similar physiological
properties, i.e., triggering C fiber membrane depolarization by opening
of cation channels permeable to calcium and sodium, are known. For
example, resiniferatoxin is described as a capsaicin analogue in U.S.
Pat. No. 5,290,816 to Blumberg. U.S. Pat. No. 4,812,446 to Brand (Procter
& Gamble Co.) describes other capsaicin analogues and methods for their
preparation. U.S. Pat. No. 4,424,205 cites capsaicin analogues. Ton et
al., Brit. J. Pharm. 10:175-182 (1955) discusses the pharmacological
actions of capsaicin and its analogues. Capsaicin, capsaicin analogues
and other capsaicinoids are also described in detail in WO 96/40079, the
disclosure of which is hereby incorporated by reference. Capsaicinoids
are also described in EP0 149 545, the disclosure of which is also hereby
incorporated by reference.

[0063]Alternatively, capsaicinoids (analogues) may be administered at the
site in replacement of, part of, or all of the dose of capsaicin, the
capsaicin analogue being administered in a therapeutically equivalent
amount of capsaicin for which it is substituted. Where a capsaicin
analogue is selected to replace some or all of the capsaicin, the
capsaicin analogue can be selected from those compounds with similar
physiological properties to capsaicin as are known in the art.
Resiniferatoxin qualitatively resembles capsaicin in its activity, but
differs quantitatively in potency (i.e. 103-104 fold more potent) and in
relative spectrum of actions. For resiniferatoxin it is recommended to
administer 0.1×10-3 to 5×10-2 mg/kg, preferably
0.1×10-3 to 5×10-3 mg/kg, body weight of the subject for
single application, or less upon multiple application. In certain
embodiments, resiniferatoxin is administered in the range of 1×10-5
mg/kg to 5×10-2 mg/kg to the subject. Resiniferatoxin also shows a
somewhat different spectrum of action, providing greater relief of pain
at a given dose. Therefore, the dose of resiniferatoxin should be at
least 100 fold less than a dose of capsaicin alone.

[0065]In certain embodiments, the capsaicinoid utilized in the
compositions and methods of the invention is capsaicin itself. In certain
preferred embodiments, the capsaicin is in a purified form obtained from
the chemical purification of Capsaicin USP. In certain preferred
embodiments, the purified capsaicin used in the compositions and methods
of the invention consists essentially of the trans isomer. The
trans-isomer of capsaicin has its activity at the vanilloid receptor, and
this embodiment, the methods and formulation of the present invention are
especially useful for treating disorders or pain that can be alleviated
through activation of the vanilloid receptors via the VR-1 mechanism.
Whereas Capsaicin USP contains only about 55-60% trans-capsaicin, with
the remainder comprising the precursors dihydrocapsaicin and
nordihydrocapsaicin, in such embodiments the formulation preferably
consists essentially of trans-capsaicin, e.g., preferably having a purity
of greater than about 97%, preferably greater than about 98%, more
preferably greater than about 99% trans-capsaicin.

[0066]The trans isomer is preferably prepared in accordance with the
method for synthesizing the trans isomer of capsaicin from a four step
process and purified as describe in U.S. Provisional Application No.
60/461,164 filed Apr. 8, 2003, the disclosure of which is hereby
incorporated by reference in its entirety. In accordance with U.S.
Provisional Application No. 60/461,164 said method for synthesizing the
trans isomer of capsaicin comprises a) alkylating 3-methyl butyne with
halovaleric acid and/or -haloalkanic acid to obtain 8-methyl-6-nonynoic
acid and/or alkynoic acid analogues thereof; b) reducing said
8-methyl-6-nonynoic acid to obtain trans-8-methyl-nonenoic acid; c)
activating the 8-methyl-nonenoic acid to obtain an acid chloride; and d)
acylating 4-hydroxy-3-methoxybenzylamine hydrochloride with the acid
chloride to obtain trans-capsaicin.

[0067]In certain embodiments, step a) of the method for preparation of the
capsaicin for use in the present invention comprises the steps of: i)
mixing anhydrous tetrahydrofuran (THF) with hexamethylphosphoramide
(HMPA) and cooling the mixture to about -78° C. to about
-75° C.; ii) adding to the mixture of step i) 3-methyl butyne
followed by a dropwise addition of a base at a temperature from about
-78° C. to about -65° C. to obtain a second mixture; iii)
warming the second mixture up to about -30° C. and stirring for
about 30 minutes; and iv) adding dropwise a solution of a halovaleric
acid in anhydrous tetrahydrofuran at a temperature of about -30°
C. for about 10 to about 15 minutes, then gradually warming to room
temperature and stirring overnight to obtain a reaction mixture.

[0068]In certain other embodiments, there is provided a method for
obtaining a crude step a) intermediate product further comprising the
steps of: i) adding 3M hydrochloric acid (HCl) to a reaction mixture and
extracting the reaction mixture with ethyl acetate; and ii) washing the
extracted reaction mixture with brine to yield a crude product.

[0069]In certain embodiments, step b) of the method for preparation of the
capsaicin for use in the present invention comprises the steps of: i)
dissolving said 8-methyl-6-nonynoic acid in a mixture of anhydrous
tetrahydrofuran and tertiary-butyl alcohol (t-BuOH) to obtain a solution
and cooling the solution to about -55° C. to about -40° C.;
ii) condensing ammonia (NH3) to the solution to a temperature of about
-50° C. to about -40° C.; iii) adding sodium drips
piece-wise and stirring from about 30 minutes to about 2 hours at a
temperature from about -45° C. to about -30° C., and iv)
adding ammonium chloride (NH4Cl), warming to room temperature and
allowing the NH3 to evaporate overnight to obtain a reaction mixture.
Step iii) of the step b) reaction may further comprise adding piece-wise
lithium and stirring from about 30 minutes to about 2 hours at a
temperature from about -65 C to about -45 C.

[0070]In certain other embodiments crude step b) intermediate product
further comprises the steps of: i) adding water to a reaction mixture;
ii) acidifying the reaction mixture with 6N HCl to a pH of about 2 to
about 3; iii) extracting the reaction mixture with ethyl acetate, washing
with brine and drying over anhydrous sodium sulfate (Na2SO4); and iv)
filtering and removing solvents under vacuum to obtain a crude step b)
intermediate product.

[0071]In certain embodiments, step c) of the method for preparation of the
capsaicin for use in the present invention comprises the steps of: i)
adding dropwise a thionyl halide to the 8-methyl-nonenoic acid at room
temperature for about 15 minutes to about 30 minutes to form a solution;
ii) heating the solution at about 50° C. to about 75 C for a
period of about 1 hour; and iii) removing excess thionyl halide under
vacuum at about 4° C. to about 45 C to obtain a step c)
intermediate product.

[0072]In certain embodiments, step d) of the method for preparation of the
capsaicin for use in the present invention comprises the steps of: i)
mixing 4-hydroxy-3-methoxy benzylamine hydrochloride and
dimethylformamide (DMF); ii) adding portion-wise at room temperature to
the mixture of step i) 5N sodium hydroxide (NaOH) and stirring for about
30 minutes; iii) adding acid halide in anhydrous ether dropwise at a
temperature of about 0° C. to about 10° C. for about 20
minutes to about 1 hour; and, thereafter, iv) gradually warming the
mixture to room temperature and stirring overnight. In certain
embodiments step d) further comprises the steps of: i) adding water to
the mixture and extracting the mixture with ethyl acetate to obtain an
ethyl acetate extract; ii) washing said extract with 1N HCl and,
thereafter, washing with sodium bicarbonate (NaHCO3); iii) washing the
solution with brine and drying over anhydrous sodium sulfate (Na2SO4);
and iv) filtering and removing solvents under vacuum to obtain a crude
product.

[0073]In certain preferred embodiments, the method of preparing the
trans-capsaicin or capsaicin intermediate after one or more of the steps
(e.g., a), b), c) and/or d)) further comprises purifying the crude
product by column chromatography, flash chromatography, or the like,
using silica gel and eluting with a mixture of ethyl acetate/hexane to
obtain a crude trans-capsaicin product.

[0074]Preferably after the capsaicin is formed via the 4 step process as
described above, the trans-capsaicin product is subjected to purification
process comprising the steps of: i) dissolving the crude trans-capsaicin
product in a mixture of ether/hexane and heating the mixture to about
40° C. to about 45° C.; ii) cooling the mixture to room
temperature while stirring for about 2 hours; and iii) filtering the
mixture to provide a purified trans-capsaicin product.

[0075]Alternatively, or additionally to the purification process(es) as
described above, the capsaicin is subjected to a further purification
process also referred to as a "semi-prep purification" or
"semi-preparative purification" of capsaicin. In the semi-prep
purification, the capsaicin or previously purified capsaicin is purified
via the use of a semi-preparative HPLC (high performance liquid
chromatography), which preferably provides for a trans-capsaicin product
having a purity of greater than about 97%, preferably greater than about
98%, more preferably greater than about 99% capsaicin.

[0076]In certain preferred embodiments, the active ingredient in the
preparation comprises substantially pure trans-capsaicin (e.g. having no
more than about 10% precursors or other capsaicin compounds such as
cis-capsaicin). In more preferred embodiments, the preparation includes
at least about 95% pure trans-capsaicin. In most preferred embodiments,
the preparation includes at least about 99% pure trans-capsaicin. While
the cis-isomer of capsaicin has activity via a number of mechanisms, VR-1
is not considered to comprise a major effect of this agent.

[0077]In view of the collective activity of the trans-isomer of capsaicin
at the VR-1 receptor, it is contemplated that it is possible in certain
embodiments of the present invention that the amount of trans-capsaicin
included in the methods and formulations of the present invention will be
reduced in comparison to a preparation which includes a less pure form of
capsaicin (e.g., capsaicin USP).

[0078]In other embodiments of the present invention, the formulations and
methods of the invention contemplate the use of a capsaicin agent
consisting essentially of cis-capsaicin.

[0079]Capsaicin, in either crude extract form, Capsaicin USP, or as
purified capsaicin, has been comprehensively studied in a variety of
tests in vitro, and in several animal species in vivo. Administration of
a single dose of capsaicinoid according to the methods of the present
invention minimizes and/or prevents systemic delivery of the capsaicin
for the purposes of: a) producing a selective, highly-localized
destruction or incapacitation of C-fibers and/or A-delta fibers in a
discrete, localized area responsible for the initiation of pain (e.g.,
intra-articular joints, intrabursally) for the purpose of reducing or
eliminating pain arising from a discrete locus (i.e., producing
antinociception), and b) minimizing potential adverse consequences of
C-fiber and/or A-delta activation and or damage outside of the locus of
pain (i.e., damage to homeostatic mechanisms, such as cardiac reflex
[e.g., Bezold-Jarisch reflex] or micturation reflex [e.g., urge to void]
or to nerve fibers in the central nervous system). The analgesic effect
preferably provides pain relief for at least about 48 to about 120 hours,
preferably from about 10 to about 21 days, more preferably from about 4
to about 5 weeks, even more preferably for at least about 6 to about 8
weeks, and most preferably for at least about 16 weeks or more.

[0080]Delivery systems can also be used to administer capsaicin and local
anesthetics that produce modality-specific blockade, as reported by
Schneider, et al., Anesthesiology, 74:270-281 (1991), or possess
physical-chemical attributes that make them more useful for sustained
release then for single injection blockade, as reported by Masters, et
al., Soc. Neurosci. Abstr., 18:200 (1992), the teachings of which are
incorporated herein. An example of a delivery system includes
microspheres wherein the anesthetic is incorporated into a polymer matrix
in a percent loading of 0.1% to 90% by weight, preferably 5% to 75% by
weight. It is possible to tailor a system to deliver a specified loading
and subsequent maintenance dose by manipulating the percent drug
incorporated in the polymer and the shape of the matrix, in addition to
the form of local anesthetic (free base versus salt) and the method of
production. The amount of drug released per day increases proportionately
with the percentage of drug incorporated into the matrix (for example,
from 5 to 10 to 20%). Other forms of delivery systems include
microcapsules, slabs, beads, and pellets, which in some cases can also be
formulated into a paste or suspension.

[0081]The delivery systems are most preferably formed of a synthetic
biodegradable polymer, although other materials may also be used to
formulate the delivery systems, including proteins, polysaccharides, and
non-biodegradable synthetic polymers. It is most preferable that the
polymer degrade in vivo over a period of less than a year, with at least
50% of the polymer degrading within six months or less. Even more
preferably, the polymer will degrade significantly within a month, with
at least 50% of the polymer degrading into non-toxic residues which are
removed by the body, and 100% of the capsaicin and anesthetic being
released within a two week period. Polymers should also preferably
degrade by hydrolysis by surface erosion, rather than by bulk erosion, so
that release is not only sustained but also linear. Polymers which meet
this criteria include some of the polyanhydrides, poly(hydroxy acids)
such as co-polymers of lactic acid and glycolic acid wherein the weight
ratio of lactic acid to glycolic acid is no more than 4:1 (i.e., 80% or
less lactic acid to 20% or more glycolic acid by weight), and
polyorthoesters containing a catalyst or degradation enhancing compound,
for example, containing at least 1% by weight anhydride catalyst such as
maleic anhydride. Other polymers include protein polymers such as gelatin
and fibrin and polysaccharides such as hyaluronic acid. Polylactic acid
is not useful since it takes at least one year to degrade in vivo. The
polymers should be biocompatible. Biocompatibility is enhanced by
recrystallization of either the monomers forming the polymer and/or the
polymer using standard techniques.

[0082]Other local carrier or release systems can also be used, for
example, the lecithin microdroplets or liposomes of Haynes, et al.,
Anesthesiology 63, 490-499 (1985), or the polymer-phospholipid
microparticles of U.S. Pat. No. 5,188,837 to Domb.

[0083]Methods for manufacture of suitable delivery systems for
administration of capsaicin alone or together with the local anesthetic
are known to those skilled in the art. The formulations may also be
designed to deliver both the anesthetic and the capsaicin, either
simultaneously or sequentially.

[0084]The local anesthetic can preferably be administered by direct
injection, implantation or infiltration to the site where the capsaicin
or capsaicin analogue is to be administered, for example, by
administering the local anesthetic directly in the diseased or pain
producing structure or the injured nerve or the nerve that provides
innervation to the painful area, or to effect a regional block of the
area including the site where the capsaicin is to be administered.

[0085]In another embodiment, the local anesthetic can preferably be
administered by injection or implantation of the anesthetic into the
epidural space adjacent to the spine for pain originating below a
patient's waist, or directly into a joint for pain originating above the
patient's waist. The prior administration of a proximal neural block
sufficiently desensitizes C fibers to the expected pungent side effects
of the subsequent capsaicin administration.

[0086]In the embodiment wherein the anesthetic is administered as
microspheres, the microspheres may be injected, implanted or infiltrated
through a trochar, or the pellets or slabs may be surgically placed
adjacent to nerves, prior to surgery or following repair or washing of a
wound. The microspheres can be administered alone when they include both
the capsaicin and local anesthetic or in combination with a solution
including capsaicin in an amount effective to prolong nerve blockade by
the anesthetic released from the microspheres. The suspensions, pastes,
beads, and microparticles will typically include a pharmaceutically
acceptable liquid carrier for administration to a patient, for example,
sterile saline, sterile water, phosphate buffered saline, or other common
carriers.

[0087]The expected side effects of the dose of capsaicin are believed to
be from the intense nociceptor discharge occurring during the excitatory
phase before nociceptor desensitization. However, the prior
administration of an anesthetic, such as a nerve block, proximally or
directly to the site of administration, eliminates or substantially
reduces such side effects. If some "breakthrough pain" occurs despite the
anesthetic, this pain may be treated by administering an analgesic such
as a nonsteroidal anti-inflammatory agent or narcotic analgesic (i.e.,
the various alkaloids of opium, such as morphine, morphine salts, and
morphine analogues such as normorphine). The administration of the
capsaicin can be repeated if necessary.

[0088]The administration of the anesthetic along with the subsequent
administration of capsaicin or capsaicin-like compounds alleviates pain
at the site for a prolonged period of time. Patients can be monitored for
pain relief and increased movement, in the situation where treatment is
in a joint. The treatment can be repeated as necessary to control the
symptoms.

[0089]The compositions and methods of the present invention can be used
for treating various conditions associated with pain by providing pain
relief at a specific site, a surgical site or open wound. Examples of
conditions to be treated include, but are not limited to, nociceptive
pain (pain transmitted across intact neuronal pathways), neuropathic pain
(pain caused by damage to neural structures), pain from nerve injury
(neuromas and neuromas in continuity), pain from neuralgia (pain
originating from disease and/or inflammation of nerves), pain from
myalgias (pain originating from disease and/or inflammation of muscle),
pain associated with painful trigger points, pain from tumors in soft
tissues, pain associated with neurotransmitter-dysregulation syndromes
(disruptions in quantity/quality of neurotransmitter molecules associated
with signal transmission in normal nerves) and pain associated with
orthopedic disorders such as conditions of the foot, knee, hip, spine,
shoulders, elbow, hand, head and neck that require surgery.

[0090]The receptors involved in pain detection are aptly enough referred
to as nociceptor-receptors for noxious stimuli. These nociceptors are
free nerve endings that terminate just below the skin as to detect
cutaneous pain. Nociceptors are also located in tendons and joints, for
detection of somatic pain and in body organs to detect visceral pain.
Pain receptors are very numerous in the skin, hence pain detection here
is well defined and the source of pain can be easily localized. In
tendons, joints, and body organs the pain receptors are fewer. The source
of pain therefore is not readily localized. Apparently, the number of
nociceptors also influences the duration of the pain felt. Cutaneous pain
typically is of short duration, but may be reactivated upon new impacts,
while somatic and visceral pain is of longer duration. It is important to
note that almost all body tissue is equipped with nociceptors. As
explained above, this is an important fact, as pain has primary warning
functions. If we did not feel pain and if pain did not impinge on our
well-being, we would not seek help when our body aches. Nociceptive pain
preferably includes, but is not limited to post-operative pain, cluster
headaches, dental pain, surgical pain, pain resulting from severe burns,
postpartum pain, angina, genitor-urinary tract pain, pain associated with
sports injuries (tendonitis, bursitis, etc. . . . ) and pain associated
with joint degeneration and cystitis.

[0091]Neuropathic pain generally involves abnormalities in the nerve
itself, such as degeneration of the axon or sheath. For example, in
certain neuropathies the cells of the myelin sheath and/or Schwann cells
may be dysfunctional, degenerative and may die, while the axon remains
unaffected. Alternatively, in certain neuropathies just the axon is
disturbed, and in certain neuropathies the axons and cells of the myelin
sheath and/or Schwann cells are involved. Neuropathies may also be
distinguished by the process by which they occur and their location (e.g.
arising in the spinal cord and extending outward or vice versa). Direct
injury to the nerves as well as many systemic diseases can produce this
condition including AIDS/HIV, Herpes Zoster, syphilis, diabetes, and
various autoimmune diseases. Neuropathic pain is often described as
burning, or shooting type of pain, or tingling or itching pain and may be
unrelenting in its intensity and even more debilitating than the initial
injury or the disease process that induced it.

[0094]Neurotransmitter-dysregulation pain syndromes, rather than involving
abnormal or damaged nerves, result from normal nerves having disruptions
in the quantity and/or quality of the various neurotransmitter molecules
associated with signal transmission from one neuron to another. More
specifically, sensory transmitters are released from the afferent nerve
ending of one nerve cell and received by receptors at the afferent end of
another nerve cell. They are chemical messengers which transmit the
signal. There are numerous transmitters, including glutamate, serotonin,
dopamine, norepinephrine, somatostatin, substance P, calcitonin
gene-related peptide, cholecystokinin, opiates and saponins. Alterations
in the quantity of transmitters and neuropeptide release, changes in the
afferent receptor, changes of re-uptake of the transmitter and/or
neuropeptides can all yield qualitative change of the neural signaling
process. As a result, the aberrant signal transmission is interpreted by
the body as pain. A representative neurotransmitter dysregulation
syndrome that may be treated by the present invention includes
fibromyalgia, which is a common condition characterized by a history of
chronic generalized pain and physical exam evidence of at least 11 of 18
defined "tender point" sites in muscles and connective tissue (Wolfe et
al., Arthritis Rheum 33:160-72, 1990). Commonly associated conditions
include irritable bowel syndrome, headache, irritable bladder syndrome
(interstitial cystitis), sleep disturbance, and fatigue (Goldenberg,
Current Opinion in Rheumatology 8:113-123, 1996; Moldofsky et al.,
Psychosom Med 37:341-51, 1975; Wolfe et al., 1990; Wolfe et al., J Rheum
23:3, 1996; Yunus et al., Semin Arthritis Rheum 11:151-71, 1981).

[0095]A predominant theory regarding the etiology of fibromyalgia holds
that an imbalance and/or dysregulation of neurotransmitter function may
occur within the central nervous system (CNS), either in the brain or
spinal cord and in the relation of the CNS to muscle and connective
tissue via regulatory nerve pathways (Goldenberg, 1996; Russell, Rheum
Dis Clin NA 15:149-167, 1989; Russell et al., J Rheumatol 19:104-9, 1992;
Vaeroy et al., Pain 32:21-6, 1988; Wolfe et al., 1996). Neurotransmitters
are chemical messengers, amino acids, biogenic amines and neuropeptides,
emitted from nerve cells that interact with receptors on other nerve
cells, as well as other cell types, including muscle and immune cells.
Neurotransmitter imbalance, which leads to increased pain experience, may
include a qualitative and/or quantitative decrease in the function of
such neurotransmitters as glutamate, serotonin, dopamine, norepinephrine,
somatostatin, substance P, calcitonin gene-related peptide,
cholecystokinin, opiates and saponins. Fibromyalgia is characterized by a
relative deficit of serotonin effect and relative excess of substance P
effect. This imbalance results in amplified modulation of pain-signaling
in the central nervous system, resulting in neurogenic pain
(Matucci-Cerinic, Rheumatic Disease Clinics of North America 19:975-991,
1993; Bonica, The Management of pain, Lea and Febiger, 2d ed.,
Philadelphia, pp. 95-121, 1990). Similar mechanisms may be at work to
cause associated conditions; for example, dysregulation of
neurotransmitter signaling in the bowel musculature, leading to irritable
bowel syndrome symptoms such as cramping, diarrhea, and/or constipation.

[0096]Neurotransmitter-dysregulation pain syndromes include, but are not
limited to the following: generalized syndromes, localized syndromes;
craniofacial pain; vascular disease; rectal, perineum and external
genitalia pain; and local syndromes of the leg/foot.

[0098]Pain Intensity assessment scales are typically used by those of
ordinary skill in the art to evaluate analgesic choices and therapeutic
effects.

[0099]A Visual Analogue Scale (VAS) is a measurement instrument that
measures a characteristic that is believed to range across a continuum of
values and cannot easily be directly measured. For example, the amount of
pain that a patient feels ranges across a continuum from none to an
extreme amount of pain may be indirectly measured via the use of a VAS.
Operationally a VAS is usually a horizontal line, 100 mm in length,
anchored by word descriptors at each end, for example "no pain" at one
end and "very severe pain" at the other end. The patient, marks on the
line the point that they feel represents their perception of their
current state. The VAS score is determined by measuring in millimeters
from the left hand end of the line to the point that the patient marks.
The 100-mm visual analog scale (VAS), a unidimensional scale that is
versatile and easy to use, has been adopted in many settings.

[0100]The capsaicinoid formulations and methods described herein may be
used to treat many conditions where the capsaicinoid can be administered
via injection, implantation or infiltration into a specific site, a
surgical site or open wound of the patient, including but not limited to
the treatment of acute or chronic pain, nociceptive and neuropathic pain,
pre- and post-operative pain, cancer pain, pain associated with
neurotransmitter dysregulation syndromes and orthopedic disorders,
sports-related injuries, acute traumatic pain, nociceptive pain, and
neurotransmitter-dysregulation syndromes.

Treatment of Chronic Post-Herniorrhaphy Pain

[0101]In a preferred embodiment, the capsaicinoid formulations and methods
disclosed herein can be used for the treatment/attenuation of chronic
post-herniorrhaphy pain. Chronic post-herniorrhaphy pain occurs in
between 5-30% of patients, with social consequences limiting some type of
activity in about 10% of patients and 1-4% of patients are referred to
chronic pain clinics. Nerve damage is probably the most plausible
pathogenic factor, but specific principles for therapy have not been
evidence-based and range from usual analgesics to re-operation with mesh
removal and various types of nerve sections without any demonstrated
efficacy in sufficient follow-up studies with or without randomized data.
In patients suffering from pain associated with chronic
post-herniorrhapy, the dose of capsaicinoid can be administered to the
site where the surgery was performed or to the immediate area surrounding
the incision.

Treatment of Pain Associated with Morton's Neuroma

[0102]In another preferred embodiment, the capsaicinoid formulations and
methods disclosed herein can be used for the treatment/attenuation of
pain associated with Morton's Neuroma. Morton's Neuroma is considered to
be most likely a mechanically induced degenerative neuropathy which has a
strong predilection for the third common digital nerve in middle-aged
women. It is considered a well-defined model of neuropathic pain. The
usual medical treatment of Morton's neuroma includes local injection of
steroids, often with lidocaine. When nonsurgical means fail to relieve
patient's symptoms, surgical removal of this offending neuroma through a
dorsal approach can produce dramatic relief of symptoms in approximately
80% of patients. However, 20% of patients experience neuroma recurrence
(referred to as stump or amputation neuroma) that often causes more
severe pain that the original neuroma and is generally treatment
resistant. Administration of capsaicinoid in accordance with the
invention is useful for the treatment of the neuropathic pain associated
with Morton's Neuroma and may reduce the re-occurrence of pain associated
with stump or amputation neuroma.

Treatment of Pain Associated with Mastectomy

[0103]In a preferred embodiment, the capsaicinoid formulations and methods
disclosed herein can be used for the treatment/attenuation of pain
associated with mastectomy. Mastectomy results in significant pain and
requires substantial doses of opioids postoperatively. Analgesic
techniques that provide good pain control while minimizing opioid side
effects are thus highly desirable. The administration of capsaicinoid in
a patient requiring a mastectomy may reduce the amount of opioid
consumption and postoperative pain scores associated with the procedure.
In patients requiring a mastectomy, the dose of capsaicinoid can be
administered to the site where the surgery was performed or to the
muscle, tissue and bones surrounding the surgical site.

Treatment of Pain Associated with Median Sternotomy

[0104]In another preferred embodiment, the capsaicinoid formulations and
methods disclosed herein can be used for the treatment/attenuation of
pain associated with median sternotomy. Median sternotomy is performed in
patients undergoing cardiac, pulmonary, or mediastinal surgery for
various indications. The procedure is performed through a vertical
midline incision over the sternum. After dividing the overlying midline
fascia and muscle the sternum is divided in its midline, from the sternal
notch to the xiphoid process, using either a sternal saw or a Lebsche
knife. Bleeding edges in the periosteum are controlled with point
electrocautery. Hemostasis of the marrow may be achieved using bone wax
or a Gel-foam/Thrombin mixture pressed into the marrow. A sternal
retractor is then placed to spread the sternal edges apart and to
maintain the surgical exposure. The dose of capsaicinoid can be
administered directly to the sternal edges, the muscle and/or tissue
surrounding the surgical site or directly to the bone (e.g., sternum). At
completion of the procedure the sternal edges are reapproximated with
stainless steel wire. The remaining wound is closed in fascial layers.
Median sternotomy results in sternal instability and pain requiring not
only substantial doses of opioids postoperatively, but also substantial
amounts of nursing and physical therapy time in order to ambulate the
patients. Analgesic techniques that provide good pain control while
minimizing opioid side effects are thus highly desirable. The
administration of a capsaicinoid in a patient requiring a median
sternotomy may reduce the amount of opioid consumption and postoperative
pain scores associated with the procedure.

Orthopedic Disorders

[0105]The capsaicinoid formulations and methods disclosed herein may be
utilized to treat/attenuate pain associated with orthopedic disorders.
Orthopedic disorders treatable via the use of the formulations and
methods of the invention include but are not limited to disorders of the
knee, shoulders, back, hip, spine, elbows, foot, hand and other
disorders, which involve pain at a specific site or body space.
Orthopedic disorders affecting these locations include, but are not
limited to bursitis, tendonitis, osteoarthritis, and rheumatoid
arthritis.

[0106]A. Bursitis

[0107]Bursitis is the inflammation of a bursa. Bursae are saclike cavities
or potential cavities that contain synovial fluid located at tissue sites
where friction occurs (e.g., where tendons or muscles pass over bony
prominences). Bursae facilitate normal movement, minimize friction
between moving parts, and may communicate with joints. In the normal
state, the bursa provides a slippery surface that has almost no friction.
A problem arises when a bursa becomes inflamed. The bursa loses its
gliding capabilities, and becomes more and more irritated when it is
moved. When the condition called bursitis occurs, the slippery bursa sac
becomes swollen and inflamed. The added bulk of the swollen bursa causes
more friction within already confined spaces. Also, the smooth gliding
bursa becomes gritty and rough. Movement of an inflamed bursa are painful
and irritating. Bursitis usually occurs in the shoulder (subacromial or
subdeltoid bursitis). Other sites include the olecranoh (miners' elbow),
prepatellar (housemaid's knee) or suprapatellar, retrocalcaneal
(Achilles), iliopectineal (iliopsoas) of the hip, ischial (tailor's or
weaver's bottom) of the pelvis, greater trochanteric of the femur, and
first metatarsal head (bunion). Bursitis may be caused by trauma, chronic
overuse, inflammatory arthritis (eg, gout, rheumatoid arthritis), or
acute or chronic infection (eg, pyogenic organisms, particularly
Staphylococcus aureus; tuberculous organisms, which now rarely cause
bursitis). Orthopedic disorders of the foot include, but are not limited
to, heel spurs, corns, bunions, Morton's neuroma, hammertoes, ankle
sprain, fractures of the ankle or metatarsals or sesamoid bone or toes,
plantar fascitis and injuries to the achilles tendon. Orthopedic
disorders of the hand include, but are not limited to, arthritis, carpal
tunnel syndrome, ganglion cysts, tendon problems such as lateral
epicondylitis, medial epicondylitis, rotator cuff tendonitis,
DeQuervian's tenosynovitis, and trigger finger/trigger thumb. Other
orthopedic disorders include, but are not limited to, Paget's disease,
scoliosis, soft-tissue injuries such as contusions, sprains and strains,
long bone fractures and various other sports injuries some of which
include patellar tendonitis and lumbar strain.

[0108]Treatment of non-infected acute bursitis has mainly consisted of
temporary rest or immobilization and high-dose NSAIDs, sometimes narcotic
analgesics, may be helpful. Voluntary movement should be increased as
pain subsides. Pendulum exercises are particularly helpful for the
shoulder joint. Aspiration and intrabursal injection of depot
corticosteroids 0.5 to 1 ml (triamcinolone diacetate 25 or 40 mg/ml)
mixed with at least 3 to 5 ml of local anesthetic after infiltration with
1% local anesthetic (e.g., lidocaine) is the treatment of choice when
rest alone is inadequate. The depot corticosteroid dose and volume of
mixture are gauged to the size of the bursa. Respiration and injection
may be required with resistant inflammation. Systemic corticosteroids
(prednisone 15 to 30 mg/day or equivalent for 3 days) are occasionally
indicated in resistant acute cases after infection and gout have been
excluded. Chronic bursitis is treated as acute bursitis, except that
splinting and rest are less likely to be helpful. Surgery is rarely
needed to treat bursitis and is usually done only in the chronic cases
that have not improved with traditional therapy. The most common surgical
treatment, if needed, is an Incision and Drainage (called an I and D) and
is used only in cases of infected bursa. The surgeon first numbs the skin
with an anesthetic and then opens the bursa with a scalpel. Finally, the
surgeon drains the fluid present in the inflamed bursa. Sometimes it is
necessary to excise the entire bursa surgically. This is indicated only
if the bursal swelling causes problems.

[0109]The capsaicinoid may be administered via injection in a location and
fashion similar to that currently utilized with respect to localized
injections of corticosteroids. For example, in certain embodiments, the
dose of capsaicin is administered by intra-articular injection into the
bursa.

[0110]In another embodiments, the capsaicinoid may be administered via
infiltration into the bursa and/or the tissue and muscle surrounding the
bursa.

[0111]B. Tendonitis

[0112]The capsaicinoid formulations and methods disclosed herein may be
utilized to treat/attenuate pain associated with tendonitis (inflammation
of the tendons) and tendonitis surgery. When tendons become inflamed, the
action of pulling the muscle becomes irritating and painful. The cause is
often unknown. Most instances tendonitis occurs in middle-aged or older
persons as the vascularity of tendons attenuates; repetitive microtrauma
may increase injury. Repeated or extreme trauma (short of rupture),
strain, or excessive (unaccustomed) exercise is most frequently
implicated. The most common cause of tendonitis is overuse. Commonly,
individuals begin an exercise program, or increase their level of
exercise, and begin to experience symptoms of tendonitis. The tendon is
unaccustomed to the new level of demand, and this overuse will cause an
inflammation and tendonitis. Tendonitis produces pain, tenderness and
stiffness near a joint which is aggravated by movement.

[0113]General practitioners commonly use non-steroidal anti-inflammatory
drugs NSAIDs) to treat tennis elbow, but there are no trials to date that
have compared them with other painkillers and one study found no
clinically important benefit over placebo. Symptomatic relief is provided
by rest or immobilization (splint or cast) of the tendon, application of
heat for chronic inflammation or cold for acute inflammation (whichever
benefits the patient should be used), local analgesic drugs, and NSAIDs
for 7 to 10 days. A critical review of the role of various
anti-inflammatory medications in tendon disorders found limited evidence
of short-term pain relief and no evidence of their effectiveness in
providing even medium term clinical resolution. Use of corticosteroid
injections provides mixed results in relief of pain and at times
insufficient evidence to support their use. Injection of the tendon
sheath with a depot corticosteroid (eg, dexamethasone acetate,
methylprednisolone acetate, hydrocortisone acetate) 0.5 to 1 mL mixed
with an equal or double volume of 1% local anesthetic (eg, lidocaine) has
been utilized as a treatment, depending on severity and site. The
injection is made blindly or proximal to the site of maximum tenderness
if the specific inflammation site cannot be identified. Particular care
should be taken not to inject the tendon per se (which offers greater
resistance) because it may be weakened and rupture in active persons.
Reexamination of a less inflamed site 3 or 4 days later often discloses
the specific lesion, and a second injection can be made with greater
precision. Rest of the injected part is advisable to diminish risk of
tendon rupture. Although complications associated with intrarticular and
soft tissue steroid injection are relatively uncommon, when a
complication does occur, it can result in severe and disabling
consequences for the subject. A small proportion of subjects fail to
respond to only one injection of corticosteroid and some subjects who
initially improve at four weeks had worst symptoms by six months.
Therefore with this lack of consensus, no good evidence to support the
use of local corticosteroid injections and the unknown long-term
side-effects of using steroids, an alternative treatment must be sought.
Surgery is rarely necessary, except for release of fibro-osseous tunnels
(as in de Quervain's disease) or for tenosynovectomy of chronic
inflammation (as in rheumatoid arthritis).

[0114]In one embodiment of the present invention, pain associated with
tendonitis of the knee, shoulders, hip, pelvis, spine, elbows, leg and
foot is treated with a capsaicinoid injection undertaken in similar
fashion as a localized corticosteroid injection. For example, in
embodiments where the capsaicinoid formulation is used for the
treatment/attenuation of pain associated with tendonitis or bursitis of
the shoulder, the dose of capsaicinoid can be administered by injection
into the subacromial bursa with the needle inserted into the space
between the acromium and the humerus on the lateral aspect of the
shoulder.

[0115]In another embodiment of the present invention, when surgery for the
treatment of tendonitis is required, pain associated with tendonitis and
tendonitis surgery of the knee, shoulders, hip, pelvis, spine, elbows,
leg and foot is treated with administration via infiltration of a
capsaicinoid directly into the affected tendon. In other embodiments, and
in addition to administration to the affected tendon, the capsaicin can
be administered by infiltration to the muscle and tissue surrounding the
affected tendon.

[0116]C. Osteoarthritis

[0117]The capsaicinoid formulations and methods disclosed herein may be
used to treat/attenuate pain associated with osteoarthritis (degenerative
joint disease) and osteoarthritis surgery. Osteoarthritis is
characterized by the breakdown of the joint's cartilage. Cartilage is the
part of the joint that cushions the ends of bones. Cartilage breakdown
causes bones to rub against each other, causing pain and loss of
movement. Most commonly affecting middle-aged and older people,
osteoarthritis can range from very mild to very severe. It affects hands
and weight-bearing joints such as knees, hips, feet and the back. There
are many factors that can cause osteoarthritis, including but not limited
to age, genetics, obesity, sports-related activities, work-related
activities, or accidents. Treatment of osteoarthritis focuses on
decreasing pain and improving joint movement, and may include: Exercises
to keep joints flexible and improve muscle strength; Many different
medications are used to control pain, including corticosteroids and
NSAIDs, glucocorticoids injected into joints that are inflamed and not
responsive to NSAIDS. For mild pain without inflammation, acetaminophen
may be used; heat/cold therapy for temporary pain relief; joint
protection to prevent strain or stress on painful joints; surgery
(sometimes) to relieve chronic pain in damaged joints; and weight control
to prevent extra stress on weight-bearing joints.

[0118]Surgical treatment to replace or repair damaged joints is indicated
in severe, debilitating disease. Surgical options include: arthroplasty
(total or partial replacement of the deteriorated joint with an
artificial joint; arthroscopic surgery to trim torn and damaged cartilage
and wash out the joint; osteotomy (change in the alignment of a bone to
relieve stress on the bone or joint); and arthrodesis (surgical fusion of
bones, usually in the spine).

[0119]Pain associated with osteoarthritis and osteoarthritis surgery may
be treated/attenuated with the capsaicinoid formulations administered via
infiltration into the affected joint, e.g., by intra-articular injection
at the affected site or by intra-articular infiltration and/or to the
tissue and muscle surrounding the affected joint, including but not
limited to osteoarthritis disorders of the knee

[0120]D. Rheumatoid Arthritis

[0121]The capsaicinoid formulations and methods disclosed herein may be
used to treat/attenuate pain associated with rheumatoid arthritis and
surgery to treat or attenuate rheumatoid arthritis. Rheumatoid arthritis
is a chronic, systemic, inflammatory disease that chiefly affects the
synovial membranes of multiple joints in the body. Because the disease is
systemic, there are many extra-articular features of the disease as well.
Rheumatoid Arthritis can affect many joints in the body, including the
knee, ankle, elbow, and wrist. Joints that are actively involved with the
disease are usually tender, swollen, and likely demonstrate reduced
motion. The disease is considered an autoimmune disease that is acquired
and in which genetic factors appear to play a role.

[0122]In patients with progressive rheumatoid arthritis, joint pathology
may occur despite appropriate conservative measures. In such patients,
loss of joint function usually causes a loss of functional ability.
Therefore, surgery is usually performed on joints that have caused the
patient a significant loss of function. Surgery is not without risks
however, and therefore the decision to operate must be carefully made.
Synovectomy is done to remove diseased portions of the joint synovium.
Ideally, this type of surgery is performed before there is destruction of
cartilage. Total joint arthroplasty is performed when there is
significant destruction of the bones forming the joint resulting in loss
of function, or there is significant pain in the joint limiting function.
"Total" means that the ends of both bones that comprise the joint have
diseased portions that are surgically removed and replaced with man-made
components (i.e., a prosthesis). The hip and knee are common sites for
total joint arthroplasty in the patient with rheumatoid arthritis and
therefore are the sites of many complications of the surgery.
Complications include: infections, dislocation, loosening of the
prosthetic components from the bone, breakage of the prosthetic
components, and fractures of bones caused by the prosthetic devices,
usually the result of a loss of bone density. In some cases where the
total joint replacement fails, the prosthetic components are removed from
the bone. In the case of the hip joint, this procedure (Girdlestone
Excision) leaves the femur without the anatomical neck or head resulting
in a soft tissue "joint" between the femur and pelvis. In some patients,
the shoulder becomes very painful and/or mechanically non-functional.
Total shoulder arthroplasty may be indicated in these patients. There is
evidence that a majority patients that have had total shoulder
arthroplasty secondary to significant pain have obtained substantial pain
relief.

[0123]There are several different classes of drugs utilized to treat
patients with the various types of rheumatic disease. These classes
include analgesics to control pain, corticosteroids, uric acid-lowering
drugs, immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, and
disease-modifying antirheumatic drugs.

[0124]Pain associated with rheumatoid arthritis and rheumatoid arthritis
surgery may be treated/attenuated with the capsaicinoid formulations
administered via infiltration into the affected joint. In other
embodiments, and in addition to administration to the affected joint, the
capsaicinoid can be administered by infiltration to the muscle and tissue
surrounding the affected joint.

[0125]E. Back Pain

[0126]The capsaicinoid formulations and methods disclosed herein may be
used to treat/attenuate pain associated with back pain. Back pain is the
second most common reason for doctor visits in the U.S. The causes of
lower back pain are numerous. Some of the more common causes of lower
back pain are: sudden injury to the back such as may occur in an auto
accident, fall, sports, or other manner; gynecological conditions such as
endometriosis, menstrual cramps, fibroid tumors, and pregnancy are
sometimes the cause of lower back pain in women; and stress to the
muscles, nerves, or ligaments in the lower back. Slipped discs, pinched
nerves, sciatica, aging, and infections are other common causes of lower
back pain. The treatment of lumbar strain consists of resting the back
(to avoid re-injury), medications to relieve pain and muscle spasm, local
heat applications, massage, and eventual (after the acute episode
resolves) reconditioning exercises to strengthen the low back and
abdominal muscles Zygapophysial joints, better known as facet or "Z"
joints, are located on the back (posterior) of the spine on each side of
the vertebrae where it overlaps the neighboring vertebrae. The facet
joints provide stability and give the spine the ability to bend and
twist. They are made up of the two surfaces of the adjacent vertebrae,
which are separated by a thin layer of cartilage. The joint is surrounded
by a sac-like capsule and is filled with synovial fluid (a lubricating
liquid that reduces the friction between the two bone surfaces when the
spine moves and also nourishes the cartilage.) A problem (such as
inflammation, irritation, swelling or arthritis) in the facet joint may
cause low back pain. Diagnostic tests can show an abnormality in a facet
joint, which may suggest that the facet joint is the source of the pain.
However, sometimes normal study results can be present while the facet
joint is still the source of pain, and abnormal results do not always
implicate the facet joint.

[0127]To determine if a facet joint is truly the source of back pain, an
injection of local anesthetic (e.g, as a block) may be utilized. If an
injection of a small amount of anesthetic or numbing medication into the
facet joint reduces or removes the pain, it indicates that the facet
joint may be the source of the pain. This is diagnostic use of the facet
joint injection. Once a facet joint is pinpointed as a source of pain,
therapeutic injections of anesthetic agents and anti-inflammatory
medications may give pain relief for longer periods of time. The
capsaicinoid formulations may be administered in such situations to
attenuate such pain.

[0128]Facet joint injections are performed while the patient is awake,
under a local anesthetic, and able to communicate. Sometimes, the health
care provider may also administer drugs to make the patient more
comfortable during the procedure. The injection is usually performed
while the patient is lying on his or her stomach on an X-ray table. EKG,
blood pressure cuffs and blood-oxygen monitoring devices may be hooked up
prior to the injection process. Once the proper site has been determined,
the physician will inject the anesthetic (often lidocaine or bupivicaine)
and the anti-inflammatory (usually a corticosteroid.). This process may
then be repeated depending on the number of affected facet joints.

[0129]F. Heel Spur

[0130]The capsaicinoid formulations and methods disclosed herein may be
used to treat/attenuate pain associated with a heel spur, which is a
projection or growth of bone where certain muscles and soft tissue
structures of the foot attach to the bottom of the heel, or heel spur
surgery. Most commonly, the plantar fascia, a broad, ligament-like
structure extending from the heel bone to the base of the toes becomes
inflamed, and symptoms of heel pain begin. As this inflammation continues
over a period of time, with or without treatment, a heel spur is likely
to form. If heel pain is treated early, conservative therapy is often
successful and surgery is usually avoided. Early signs of heel pain are
usually due to plantar fasciitis, the inflammation of the plantar fascia.
It is probably the most common cause of heel pain seen by the podiatrist.
It is seen in all groups of people; runners, athletes, week-end warriors,
people who have jobs requiring a fair amount of standing, walking, or
lifting, and those who have recently gained weight. Initially, patients
receive taping of the foot and when indicated, cortisone injections or a
short course an anti-inflammatory medication, taken orally. Exercises,
night splints, and physical therapy are used as adjunct methods to try to
reduce the inflammation. If successful, a custom made in shoe orthotic is
made to control the abnormal stress and strain on the plantar fascia
resulting in remission of the majority of the symptoms. In some
instances, conservative therapy fails, and surgery is indicated. Many
times an endoscopic procedure, called a plantar fasciotomy, is done in
which a release of some of the fibers of the plantar fascia is performed
through two, small incisions on each side of the heel. Recovery is often
2 weeks or less, with the patient walking with only a surgical shoe 24
hours after surgery. When the plantar fascia undergoes mico-herniations
(tears), a heel spur may develop. Again, if treated early, even patients
with spurs find satisfactory remission of symptoms with conservative
therapy such as padding, strapping, injections and in-shoe orthotics.
Unfortunately there are those whose symptoms are severe enough to prevent
them from performing their job or recreational activities, and surgery is
then indicated. Surgery involves releasing a part of the plantar fascia
from its insertion in the heel bone, as well as removing the spur. Many
times during the procedure, pinched nerves (neuromas), adding to the
pain, are found and removed. Often, an inflamed sac of fluid call a
accessory or adventitious bursa is found under the heel spur, and it is
removed as well. Post operative recovery is usually a slipper cast and
minimal weight bearing for a period of 2-3 weeks. On some occasions, a
removable short-leg walking boot is used or a below knee cast applied.
After they are removed normal weight-bearing is allowed and the patient
us treated with in-office physical therapy.

[0131]When a capsaicinoid is used for plantar fascia, the dose of
capsaicinoid is preferably administered by injection into the affected
area. When surgery is required, the dose of capsaicinoid is preferably
administered by infiltration into the heel bone after the surgical
incision is made and/or to the tissue and muscle surrounding the heel
bone.

Treatment of Pain Associated with Laparoscopic Cholecystectomy

[0132]In another preferred embodiment, the capsaicinoid formulations and
methods disclosed herein can be used for the treatment/attenuation of
pain associated with laparoscopic cholecystectomy. Laparoscopic
cholecystectomies have virtually replaced open surgical cholecystectomy.
However, patients undergoing laparoscopic cholecystectomies still have
pain. Pain control following surgery typically includes use of opioids,
especially within the first several days after surgery. The
administration of a capsaicinoid in a patient who has undergone a
laparoscopic cholecystectomy may reduce the amount of opioid consumption
and postoperative pain scores associated with the procedure. In patients
requiring a laparoscopic cholecystectomy, the dose of capsaicinoid can be
administered either by injection, infiltration or both injection and
infiltration. When the dose of capsaicinoid is administered by injection,
the capsaicinoid may be injected directly the site of incision or to the
immediate area surrounding the surgical site. In other embodiments, the
dose of capsaicinoid can be administered to the site where the surgery is
being performed or to the muscle, tissue and bones surrounding the
surgical site prior to closure of the wound. In certain other
embodiments, the capsaicinoid formulations and methods disclosed herein
can be used for the treatment/attenuation of pain associated with
cholecystectomy requiring a more invasive surgery than a laparoscopy.

Infiltration Dose

[0133]In preferred embodiments of the present invention, the dose of
capsaicinoid contained in a unit dose for infiltration is from about 1
μg to about 15,000 μg of capsaicin, preferably from about 600 μg
to about 15,000 μg capsaicin, more preferably from about 600 μg to
about 10,000 μg capsaicin, or a therapeutically equivalent amount of
one or more capsaicinoids. In certain preferred embodiments, the dose of
capsaicin is from about 1000 μg to about 10,000 μg, or a
therapeutically equivalent amount of one or more capsaicinoids.
Preferably, the capsaicinoid is administered in a pharmaceutically and
physiologically acceptable vehicle for injection or implantation.

[0134]In certain other embodiments, suitable doses of
capsaicin/capsaicinoid for infiltration for the treatment of nociceptive
pain, neuropathic pain, pain from nerve injury, pain from myalgias, pain
associated with painful trigger points, pain from tumors in soft tissues,
pain associated with neurotransmitter-dysregulation syndromes and pain
associated with orthopedic disorders range from about 600 μg to about
15,000 μg of capsaicin (trans 8-methyl-N-vanillyl-6-noneamide),
preferably from about 600 to about 10,000 micrograms, more preferably
from about 1000 to 10,000 micrograms, with 5,000 μg most preferred.

[0135]In certain preferred embodiments, an injection of local anesthetic
can be administered in proximity to the site prior to administration of
the capsaicinoid, e.g., as described above and in the appended examples.
In other embodiments, phenol can be used instead of or in addition to the
local anesthetic.

Injectable Dose

[0136]In preferred embodiments of the present invention, the dose of
capsaicinoid contained in a unit dose injection/implantation is from
about 1 μg to about 5000 μg of capsaicin, preferably from about 10
μg to about 3000 μg capsaicin, more preferably from about 300 μg
to about 1500 μg capsaicin, or a therapeutically equivalent amount of
one or more capsaicinoids. In certain preferred embodiments, the dose of
capsaicin is from about 400 μg to about 1200 μg, or a
therapeutically equivalent amount of one or more capsaicinoids.
Preferably, the capsaicinoid is administered in a pharmaceutically and
physiologically acceptable vehicle for injection or implantation.

[0137]In certain other embodiments, suitable doses of
capsaicin/capsaicinoid for injection or implantation for the treatment of
nociceptive pain, neuropathic pain, pain from nerve injury, pain from
myalgias, pain associated with painful trigger points, pain from tumors
in soft tissues, pain associated with neurotransmitter-dysregulation
syndromes and pain associated with orthopedic disorders range from about
1 μg to about 3000 μg of capsaicin (trans
8-methyl-N-vanillyl-6-noneamide), preferably from about 20 to about 300
micrograms, more preferably from about 35 to 200 micrograms, with 100
μg most preferred.

[0138]The administration of the anesthetic along with the subsequent
administration of the capsaicinoid formulations and methods of the
invention alleviate or attenuate pain at the site for a prolonged period
of time. With respect to joint pain, in certain preferred embodiments a
single unit dose capsaicinoid injection or implantation attenuates pain
at the site for at least about one month, more preferably at least about
3 months, and typically in certain embodiments from about 3 to about 6
months. With respect to pain associated with arthritic conditions such as
osteoarthritis, in certain preferred embodiments a single unit dose
capsaicinoid injection or implantation attenuates pain at the site for at
least about 3 months to at least about 4 months. With respect to
post-surgical pain, in certain preferred embodiments a single unit dose
capsaicinoid injection or implantation attenuates pain at the site for at
least about one week, and in certain embodiments for at least about 1
month. Patients can be monitored for pain relief and increased movement,
in the situation where treatment is in a joint. The treatment can be
repeated as necessary to control the symptoms.

[0139]In certain preferred embodiments, an injection of local anesthetic
can be administered in proximity to the site prior to administration of
the capsaicinoid, e.g., as described above and in the appended examples.
In other embodiments, phenol can be used instead of or in addition to the
local anesthetic.

Injectable/Implantable and Infiltratable Formulations

[0140]In embodiments where the capsaicinoid is administered by injection,
implantation or infiltration, the capsaicinoid is administered to a
discrete site by penetrating the outer layer of the skin or a surgical
site or wound opening by instillation or injection to the site or wound
opening (e.g., tissue, muscle, and bone) with an instrument known to
those skilled in the art for administering agents via infiltration, e.g.,
a needle and syringe.

[0142]Depending on the pharmaceutically acceptable vehicle chosen, the
dose of capsaicinoid can be administered as an aqueous solution or
suspension for injection, implantation or infiltration. Injections or
infiltrations may be separated into five distinct types, generally
classified as (i) medicaments or solutions or emulsions suitable for
infiltration; (ii) dry solids or liquid concentrates containing no
buffers, diluents, or other added substances, and which upon the addition
of suitable vehicles, yield solutions conforming in all aspects to the
requirements for infiltration; (iii) preparations as described in (ii)
except that they contain one or more buffers, diluents or other added
substances; (iv) solids which are suspended in a suitable fluid medium
and which are not to be injected intravenously or into the spinal canal;
and (v) dry solids, which upon the addition of suitable vehicles, yield
preparations conforming in all respects to the requirements of Sterile
Suspensions (see: H. C. Ansel, Introduction to Pharmaceutical Dosage
Forms, 4th Edit., 1985, pg. 238).

[0143]In certain other embodiments, a surfactant can preferably be
combined with one or more of the pharmaceutically acceptable vehicles
previously described herein so that the surfactant or buffering agent
prevents the initial stinging or burning discomfort associated with
capsaicinoid administration, as a wetting agent, emulsifier, solubilizer
and/or antimicrobial.

[0145]Buffering agents may also be used to provide drug stability; to
control the therapeutic activity of the drug substance (Ansel, Howard C.,
"Introduction to Pharmaceutical Dosage Forms," 4th Ed., 1985); and/or to
prevent the initial stinging or burning discomfort associated with
capsaicin administration. Suitable buffers include, but are not limited
to sodium bicarbonate, sodium citrate, citric acid, sodium phosphate,
pharmaceutically acceptable salts thereof and combinations thereof. When
one or more buffers are utilized in the formulations of the invention,
they may be combined, e.g., with a pharmaceutically acceptable vehicle
and may be present in the final formulation, e.g., in an amount ranging
from about 0.1% to about 20%, more preferably from about 0.5,% to about
10%.

[0146]In certain preferred embodiments, the pharmaceutical vehicle
utilized to deliver the capsaicinoid comprises polyethylene glycol,
histidine, and sucrose, in water for injection. In one preferred
embodiment, the pharmaceutical vehicle comprises about 20% PEG 300, about
10 mM histidine and about 5% sucrose in water for injection.

[0147]In other preferred embodiments, delivery systems can be used to
administer a unit dose of capsaicinoid. The dose of capsaicinoid can
preferably be administered as injectable, implantable or infiltratable
microparticles (microcapsules and microspheres). The microparticles are
preferably in a size and distribution range suitable for infiltration.
The diameter and shape of the microparticles can be manipulated to modify
the release characteristics. For example, larger diameter microparticles
will typically provide slower rates of release and reduced tissue
penetration and smaller diameters of microparticles will produce the
opposite effects, relative to microparticles of different mean diameter,
but of the same composition. In addition, other particle shapes, such as
cylindrical shapes, can also modify release rates by virtue of the
increased ratio of surface area to mass inherent to such alternative
geometrical shapes, relative to a spherical shape. The diameter of
microparticles preferably range in size from about 5 microns to about 200
microns in diameter.

[0148]In a more preferred embodiment, the microparticles range in diameter
from about 20 to about 120 microns. Methods for manufacture of
microparticles are well known in the art and include solvent evaporation,
phase separation and fluidized bed coating.

[0149]When the preferred methods of the present invention provide for
administration of a single dose of capsaicinoid alone, the single dose of
capsaicinoid is preferably administered at at a discrete site, a surgical
site or open wound in an amount effective to denervate the surgical site
or open wound without eliciting an effect outside the site or wound. The
single dose is preferably administered onto a nerve directly at the site
where pain relief is needed, directly into the pain producing structure,
or onto a nerve that provides innervation to the painful area via
infiltration. Infiltration preferably includes, but is not limited to,
administration onto the tissue, muscle or bone surrounding the surgical
site or open wound. In other embodiments, the dose of capsaicinoid may be
administered intra-articularly, intra-sternally, intrasynovially,
intra-bursally or into body spaces. Injectable or implantable
administration preferably includes, but is not limited to subcutaneous
(under the skin), intramuscular (muscle), intrathecal, epidural,
intraperitoneal, caudal, intradermal or intracutaneous (into the skin),
intercostals at a single nerve, intra-articular (joints) or body spaces,
intrasynovial (joint fluid), intraspinal (spinal column), intra-arterial
(arteries) administrations and administration into other connective
tissue compartments. As used herein "intraspinal" means into or within
the epidural space, the intrathecal space, the white or gray matter of
the spinal cord affiliated structures such as the dorsal root and dorsal
root ganglia. Infiltratable administration of the formulations of the
invention may be, e.g., into a joint selected from the group consisting
of knee, elbow, hip, sternoclavicular, temporomandibular, carpal, tarsal,
wrist, ankle, intervertebral disk, ligamentum flavum and any other joint
subject to pain. Examples of body spaces include pleura, peritoneium,
cranium, mediastinum, pericardium, and bursae or bursal. Examples of
bursae include acromial, bicipitoradial, cubitoradial, deltoid,
infrapatellar, ishchiadica, and other bursa known to those skilled in the
art to be subject to pain.

[0150]When the single dose of capsaicinoid is administered via injection,
the injection volume of capsaicin will depend on the localized site of
administration. Suitable injection volumes to be delivered preferably
range from about 0.1 to about 20 ml, more preferably from about 0.5 to
about 10 ml and most preferably from about 1.0 to about 5 ml, depending
on the site to be treated. Alternatively, when the single dose of
capsaicinoid is administered via infiltration, the volume of capsaicinoid
administered will depend on the surgical site or size of the opened
wound. Suitable infiltration volumes to be delivered preferably range
from about 0.1 to about 1000 ml, more preferably from about 1 ml to about
100 ml and most preferably from about 5 ml to about 30 ml, depending on
the site or wound opening to be treated.

[0151]The administration of the anesthetic along with the subsequent
administration of capsaicinoid alleviates pain at the discrete site, the
surgical site or wound opening for a prolonged period of time. Patients
can be monitored for pain relief and increased movement, in the situation
where treatment is in a joint. The treatment can be repeated as necessary
to control the symptoms.

[0152]In certain embodiments of the invention, an adjunctive agent can be
co-administered with the capsaicinoid. Suitable adjunctive agents for use
in the present invention include, but are not limited to non-steroidal
inflammatory agents ("NSAIDS"), non-anesthetic sodium channel blockers,
vasoconstrictors, vasodilators and tricyclic anti-depressants.

[0153]In certain embodiments of the present invention, the capsaicinoid
and the adjunctive agent are administered together in a single
composition. In other embodiments, the capsaicinoid and the adjunctive
agent are administered as separate compositions before, after or at the
same time as the capsaicinoid, by the same or different routes of
administration. For example, the adjunctive agent can be administered
orally, via implant, parenterally, sublingually, rectally, topically, or
via inhalation. When administered in separate compositions, preferably
the adjunctive agent formulation and the capsaicinoid formulation provide
overlapping duration of effect.

[0154]In certain embodiments, one or more adjunctive agents can be
co-administered with the capsaicinoid. The multiple adjunctive agents can
be selected within the same group (e.g., two NSAIDS) or from different
groups (e.g., an NSAID and a vasoconstrictor) and can be administered by
multiple routes of administration. Further a local anesthetic can be
administered with the capsaicinoid, in addition to the adjunctive agent.

[0156]NSAIDS exhibit inhibition of cyclooxygenases I and II, the enzymes
responsible for the biosynthesis of the prostaglandins and certain
related autacoids. NSAIDs are known to be antipyretic, analgesic, and
antiinflammatory. Specific classes of non-steroidals useful in the
present invention are also disclosed in detail in the following U.S.
patents, all incorporated by reference herein: U.S. Pat. No. 4,275,059,
Flora, et al, issued Jun. 23, 1983, discloses salicylic acid, its
pharmaceutically-acceptable salts, and its pharmaceutical-acceptable
esters and derivatives; U.S. Pat. No. 4,264,582, Flora, et al, issued
Apr. 28, 1981, discloses p-(isobutylphenyl)acetic acid compounds
including the parent acid (ibufenac) and its salts and esters, and
derivatives thereof, U.S. Pat. No. 4,282,214, Flora, et al, issued Aug.
4, 1981, discloses various phenylacetic acid derivatives, their
pharmaceutically-acceptable salts, and their pharmaceutically-acceptable
ester; U.S. Pat. No. 4,216,212, Flora, et al, issued Aug. 5, 1980,
discloses prazolidine compounds, their pharmaceutically-acceptable salts,
and their pharmaceutically-acceptable esters; U.S. Pat. No. 4,269,828,
Flora, et al, issued May 26, 1981, discloses indole compounds, their
pharmaceutically-acceptable salts, and their pharmaceutically-acceptable
esters.

[0157]Aspirin is the prototypical nonsteroidal anti-inflammatory agent. It
possesses analgesic-antipyrectc and anti-inflammatory properties and is
the standard for the comparison and evaluation of other nonsteroidal
anti-inflammatory agents. Aspirin is a member of the class of
nonsteroidal anti-inflammatory agents known as "the salicylates." Other
salicylates include, but are not limited to salicylic acid, methyl
salicylate, diflunisal, salsalate, olsalazine and sulfasalazine.
Administration of salicylates is generally recognized in the art for the
treatment of low intensity pain arising from integumental structures
rather than from viscera.

[0158]Another class of nonsteroidal anti-inflammatory agents is the
para-aminophenol derivatives; of which, acetaminophen (Tylenol®) and
phenacetin are members. Acetaminophen and phenacetin posses
analgesic-antipyretic activity, however, they both posses weak
anti-inflammatory activity. Therefore, these agents are a suitable
substitute for the salicylates in the treatment of low intensity pain,
but are generally not recommended for the treatment of anti-inflammatory
conditions.

[0159]In addition there are several other classes of nonsteroidal
anti-inflammatory agents. These include, but are not limited to the
propionic acid derivatives, the fenamates, the oxicams, the indole
derivatives, the pyrazolon derivatives and any combinations or mixtures
thereof.

[0166]Non-steroidal, anti-inflammatory agents (NSAIDs) exert most of their
anti-inflammatory, analgesic and antipyretic activity and inhibit
hormone-induced uterine contractions and certain types of cancer growth
through inhibition of prostaglandin G/H synthase, also known as
cyclooxygenase.

[0167]Fatty acid cyclooxygenase (COX) was described as the source of
prostaglandins, thromboxanes, and a variety of other arachidonic acid-,
and higher desaturated fatty acid-derived biologically active
hydroxylated metabolites beginning in the late 1960's. Bengt Sammuelsson,
Sune Bergstrom and their colleagues discovered the biological activity
and elucidated the structures of the products of cyclooxygenase in the
late 1960's and early 1970's and John Vane discovered that aspirin and
other NSAIDs exert their major biological activities by inhibiting
cyclooxygenase. COX is directly responsible for the formation of PGG and
PGH and these serve as the intermediates in the synthesis of PGD, PGE,
PGF, PGI, and TXA. By the late 1970's and early 1980's, it was
appreciated that many hormones and other biologically active agents could
regulate the cellular activity of COX. At first, it was assumed that COX
induction was the simple result of oxidative inactivation of COX, which
happens after only a few substrate turnovers. This is common among
enzymes that incorporate molecular oxygen into their substrates--the
oxygen rapidly degrades the enzyme. Such enzymes are sometimes referred
to as suicide enzymes. In response to the rapid (within seconds)
inactivation of cyclooxygenase, its message is transcribed, and the
enzyme is rapidly induced to replace that lost due to catalysis. It was
noticed by several groups that cyclooxygenase was induced to a much
greater degree than necessary to replace the lost enzyme. Using an
oligonucleotide directed to the cloned COX-1 enzyme, a second band was
identified on Northern blots under low stringency. This gene was cloned
and identified as a second COX enzyme, named COX-2, and was found to be
largely absent from many cells under basal conditions but rapidly induced
by several cytokines and neurotransmitters. The expression of this enzyme
was found to be largely responsible for the previously-observed excess
COX activity in activated cells. The genes for COX-1 and COX-2 are
distinct, with the gene for COX-1 being 22 kb and the message size 2.8 kb
whereas the gene for COX-2 is 8.3 kb and the message size 4.1 kb. Whereas
the COX-1 promoter does not contain recognized transcription factor
binding sites, the COX-2 promoter contains sites for NF-B, AP-2, NF-IL-6
and glucocorticoids (H. R. Herschman, Canc. Metas. Rev. 13: 256, 1994).
There are some differences in the active sites of the enzymes. Aspirin
inhibits the cyclooxygenase activity of COX-1 but leaves intact its
peroxidase activity, whereas aspirin converts COX-2 from a cyclooxygenase
to a 15-lipoxygenase (E. A. Meade et al, J. Biol. Chem. 268: 6610, 1993).

[0168]It has been proposed that the COX-1 enzyme is responsible, in many
cells for endogenous basal release of prostaglandins and is important in
the physiological functions of prostaglandins which include the
maintenance of gastrointestinal integrity and renal blood flow.
Inhibition of COX-1 causes a number of side effects including inhibition
of platelet aggregation associated with disorders of coagulation, and
gastrointestinal toxicity with the possibility of ulcerations and of
hemorrhage. It is believed that the gastrointestinal toxicity is due to a
decrease in the biosynthesis of prostaglandins which are cytoprotective
of the gastric mucosa. Thus a high incidence of side effects has
historically been associated with chronic use of classic cyclooxygenase
inhibitors, all of which are about equipotent for COX-1 or COX-2, or
which are COX-1-selective. While renal toxicity occurs, it usually
becomes evident in patients who already exhibit renal insufficiency (D.
Kleinknecht, Sem. Nephrol. 15: 228, 1995). By far, the most prevalent and
morbid toxicity is gastrointestinal. Even with relatively nontoxic drugs
such as piroxicam, up to 4% of patients experience gross bleeding and
ulceration (M. J. S. Langman et al, Lancet 343: 1075, 1994). In the
United States, it is estimated that some 2000 patients with rheumatoid
arthritis and 20,000 patients with osteoarthritis die each year due to
gastrointestinal side effects related to the use of COX inhibitors. In
the UK, about 30% of the annual 4000 peptic ulcer-related deaths are
attributable to COX inhibitors (Scrip 2162, p. 17). COX inhibitors cause
gastrointestinal and renal toxicity due to the inhibition of synthesis of
homeostatic prostaglandins responsible for epithelial mucus production
and renal blood flow, respectively.

[0169]The second form of cyclooxygenase, COX-2, is rapidly and readily
inducible by a number of agents including mitogens, endotoxins, hormones,
cytokines and growth factors.

[0170]It has been proposed that COX-2 is mainly responsible for the
pathological effects of prostaglandins, which arise when rapid induction
of COX-2 occurs in response to such agents as inflammatory agents,
hormones, growth factors, and cytokines. A selective inhibitor of COX-2
therefore would have anti-inflammatory, antipyretic and analgesic
properties similar to those of a conventional non-steroidal
anti-inflammatory drug (NSAID). Additionally, a COX-2 inhibitor would
inhibit hormone-induced uterine contractions and have potential
anti-cancer effects. A COX-2 inhibitor would have advantages over NSAIDS
such as a diminished ability to induce some of the mechanism-based side
effects. Moreover, it is believed that COX-2 inhibitors have a reduced
potential for gastrointestinal toxicity, a reduced potential for renal
side effects, a reduced effect on bleeding times and a lessened ability
to induce asthma attacks in aspirin-sensitive asthmatic subjects.

[0171]Thus, compounds with high specificity for COX-2 over COX-1, may be
useful as alternatives to conventional NSAIDS. This is particularly the
case when NSAID use is contra-indicated, such as in patients with peptic
ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis
or with a recurrent history of gastrointestinal lesions; GI bleeding,
coagulation disorders including anemia, hypoprothrombinemia, haemophelia
or other bleeding problems; kidney disease, and patients about to undergo
surgery or taking anticoagulants.

[0172]Once it became clear that COX-1 but not COX-2 is responsible for
gastrointestinal epithelial prostaglandin production and a major
contributor to renal prostaglandin synthesis, the search for selective
COX-2 inhibitors became extremely active. This led very quickly to the
recognition that several COX inhibitors, including rofecoxib (Vioxx),
celecoxib (Celebrex), DUP-697, flosulide, meloxicam, 6-MNA, L-745337,
nabumetone, nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035,
JTE-522, RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide,
D-1367, SC-5766, PD-164387, etoricoxib, valdecoxib and parecoxib or
pharmaceutically acceptable salts, enantiomers or tautomers thereof.

[0173]In certain embodiments, the amount of COX 2 selective inhibitor that
is used in accordance with the present invention preferably ranges from
about 0.001 to about 100 milligrams per day per kilogram of body weight
of the subject (mg/day kg), more preferably from about 0.05 to about 50
mg/day kg, even more preferably from about 1 to about 20 mg/day kg.

[0174]Administration of capsaicinoid alone or with a local anesthetic
sometimes times results in the patient experiencing a dull aching pain at
and around the site of local anesthetic administration. To prevent or
reduce the occurrence of this dull aching pain, the non-steroidal
antiinflammatory adjunctive agent is preferably administered prior to
capsaicinoid and local anesthetic administration. Preferably, the
non-steroidal antiinflammatory adjunctive agent is administered orally,
which also helps to avoid the discomfort of the patient receiving another
injection. Alternatively, in certain embodiments, a selective Cox-2
inhibitor can be administered peripherally by injection or infiltration.

[0175]Suitable doses of the non-steroidal antiinflammatory adjunctive
agents vary due to the wide variations in potency among the various
NSAIDs and there respective selectivity for COX-1 or COX-2 inhibition.
The dose is also dependant on the severity of the pain which must be
prevented or alleviated, the physical condition of the patient, the
relative severity and importance of adverse side effects, and other
factors within the judgment of the physician. Examples of suitable doses
and routes of administration for non-steroidal anti-inflammatory
adjunctive agents are listed in Tables IV-X below:

[0176]In certain embodiments, dosage levels of NSAIDs on the order of
about 0.05 mg/kg to about 75 mg/kg body weight per day are effective for
enhancing the desired effects of localized capsaicinoid administration
and decreasing the undesired effects, or for minimizing diffusion of
capsaicinoid from the site of administration so as to amplify either of
the preceding. Dosage levels of NSAIDs on the order of about 5 mg/kg to
about 40 mg/kg body weight per day and dosage levels of NSAIDs on the
order of about 0.1 mg/kg to about 4 mg/kg body weight per day can also be
administered.

[0182]The sodium channel blockers may be administered to mammals, e.g.
humans, orally at a dose of 0.1 to 10 mg/kg, or an equivalent amount of
the pharmaceutically acceptable salt thereof, per day of the body weight
of the mammal being treated. For carbamazepine, from about 50 to about
1500 mg/day, preferably about to about 800 mg/day, more preferably about
100 to about 600 mg/day, and most preferably about 100 to about 400
mg/day; can be orally administered. For lamotrigine, from about 50 to
about 1200 mg/day, preferably 100 to about 600 mg/day, more preferably
about 100 to about 450 mg/day, and most preferably about 100 to about 300
mg/day can be orally administered.

[0183]Many of the above contemplated non-anesthetic sodium channel blocker
adjunctive agents are described more fully in the literature, such as in
Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th
Edition), McGraw-Hill, 1993, and Drug Facts and Comparisons, Wolters
Kluwer Co. (1999).

[0184]In another embodiment of the present invention, it is preferable to
administer the non-anesthetic sodium channel blocker adjunctive agent
peripherally by injection.

[0185]In preferred embodiments, carbamazepine is the adjunctive agent and
is administered by injection or by infiltration.

[0186]Suitable doses of the non-anesthetic sodium channel blocker
adjunctive agents may vary due to the wide variations in potency among
the particular agents and there respective mechanism for decreasing
propagation and/or generation of action potentials. The dose administered
may also be dependant on the severity of the pain which must be prevented
or alleviated, the physical condition of the patient, the relative
severity and importance of adverse side effects, and other factors within
the judgment of the physician. Examples of suitable doses and routes of
administration for the various non-anesthetic sodium channel blocker
adjunctive agents are listed in Tables XI-XIII below:

[0187]In embodiments where the present invention contemplates the use of a
vasoconstrictor adjunctive agent, vasoconstrictors suitable for use in
the present invention include, but are not limited to catecholamines,
alpha-1 and alpha-2 adrenergic agonists, analogs thereof, active
metabolites thereof, and mixtures thereof. Catecholamines include, but
are not limited to epinephrine, norepinephrine, and dopamine. Alpha-1
adrenergic agonists include, but are not limited to methoxamine,
phenylephrine, mephentermine, metaraminol, mitodrine, methysergide,
ergotamine, ergotoxine, dihydroergotamine, sumatriptan, and mixtures
thereof. Alpha-2 adrenergic agonists include, but are not limited to
clonidine, guanfacine, guanabenz, methyldopa, ephedrine, amphetamine,
methamphetamine, methylphenidate, ethylnorepinephrine ritalin, pemoline
and other sympathomimetic agents including active metabolites, and
mixtures thereof.

[0188]Each of the above contemplated vasoconstricting agents is described
more fully in the literature, such as in Goodman and Gilman, The
Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1993,
Pgs. 199-225. For example, the catecholamine epinephrine is a potent
stimulant of both α- and β-adrenergic receptors. It is
considered as one of the most potent vasopressor drugs known.
Epinephrine's chief vascular action is exerted on the smaller arterioles
and precapillary sphincters, although veins and large arteries also
respond to epinephrine administration. Administration of epinephrine via
injection produces a marked decrease in cutaneous blood flow,
constricting precapillary vessels and small venules. Cutaneous
vasoconstriction produces a significant decrease in blood flow in the
hands and feet. The marked decrease in cutaneous blood flow after
intravenous administration of epinephrine contributes to epinephrine's
slow absorption from subcutaneous tissues. However, absorption of
epinephrine is more rapid after intramuscular administration.

[0189]Compounds, formulations, and dosages of the vasoconstrictors
described in this method are known in the art. In certain embodiments,
for example, vasoconstrictive compositions may be used at art-recognized
effective doses, such as, about 0.001 milligram per milliliter to about
0.01 milligram per milliliter of epinephrine.

[0190]In certain embodiments, when epinephrine is administered with an
anesthetic, preferably the epinephrine is added in an amount of 0.5 to 1
ml (1:1000) per 100 ml of anesthetic solution for a vasoconstrictive
effect. Preferably epinephrine 1; 100,000 or 1:200,000 dilution is used.

[0191]Norepinephrine, like epinephrine, is a potent agonist at
α-receptors, but it is somewhat less potent than epinephrine.
Dopamine, the immediate metabolic precursor of norepinephrine and
epinephrine, produces vasoconstriction at high concentrations, whereas,
total peripheral resistance due to vasoconstriction is practically
unchanged at low to intermediate doses due to dopamine's ability to
reduce regional arterial resistance in the mesentary and kidneys while
causing only minor increases in other vascular beds.

[0192]The existence of more than one adrenergic receptor was first
proposed in 1948 by Ahlquist. His hypothesis was based on a study of the
abilities of epinephrine, norepinephrine and other related agonists to
regulate various physiological processes. As a result of his studies, the
alpha (α) and beta (β) designations were established.

[0193]Alpha adrenergic receptors are present in many organs throughout the
human body. However, vasoconstriction is not produced in all organs. In
fact, adrenergic vasoconstriction is produced in veins and the following
arterioles: coronary, skin and mucosa, skeletal muscle, cerebral,
pulmonary, abdominal viscera, salivary glands, and renal arterioles. Only
alpha-1 receptors are found in skeletal muscle, cerebral, pulmonary, and
abdominal viscera and both alpha-1 and alpha-2 receptors are found in
coronary, skin and mucosa, salivary glands, and renal arterioles.

[0194]When the vasoconstrictor adjunctive agents used in the present
invention are co-administered with the capsaicinoids and/or local
anesthetic of the present invention, the vasoconstrictor adjunctive agent
produces a decrease in cutaneous blood flow to the area surrounding the
injection site, thus prolonging the activity of the capsaicinoid and/or
local anesthetic at the injection site.

[0195]Suitable doses of vasoconstrictor adjunctive agents may vary due to
the wide variations in potency among the particular catecholamines and
adrenergic agonist and there respective selectivity for alpha-1 or
alpha-2 adrenergic receptors. The dose administered may also be dependant
on the severity of the pain which must be prevented or alleviated, the
physical condition of the patient, the relative severity and importance
of adverse side effects, and other factors within the judgment of the
physician. Examples of suitable doses and routes of administration for
the various vasoconstrictor adjunctive agents are listed in Tables XIV-XV
below:

[0196]In embodiments where the present invention contemplates the use of a
tricyclic antidepressant adjunctive agent, the term tricyclic
antidepressant adjunctive agent ("TCA" adjunctive agent), as used herein,
represents a tricyclic antidepressant agent which can be identified as
such by the skilled artisan. Tricyclic antidepressants are known for
their use in the treatment of depression. For example, Goodman and
Gilman's "The Pharmacological Basis of Therapeutics," 9th edition,
Macmillan Publishing Co., 1996, pp 413-423, provides well known examples
of tricyclic antidepressant agents. Specific tricyclic antidepressant
agents useful in the present invention are also disclosed in detail in
The Merck Index, 12th Edition, Merck & Co., Inc.

[0201]The mechanism of action of the tricyclic antidepressant agents used
in the present invention is presumed to be due to the anticholinergic
action of the tricyclic antidepressant, whereby they block the
neurotransmitter acetylcholine to prevent transmission of impulses in the
A-delta and C pain fibers, thereby resulting in pain relief.

[0203]Suitable doses of the tricyclic antidepressant adjunctive agents
vary due to the wide variations in potency among the various TCAs. The
dose is also dependant on the severity of the pain which must be
prevented or alleviated, the physical condition of the patient, the
relative severity and importance of adverse side effects, and other
factors within the judgment of the physician. Examples of suitable doses
and routes of administration of tricyclic antidepressant adjunctive
agents are listed in Table XVI below:

[0204]In embodiments where the present invention contemplates the use of a
vasodilator, e.g., a nitrate vasodilator. Nitrate vasodilators include,
but are not limited to nitrites, organic nitrates, nitroso compounds and
any other nitrogen oxide-containing substances.

[0205]As capsaicinoids are highly protein bound, vasodilators are useful
as adjunctive agents as they facilitate the capsaicinoid being diffused
throughout the desired site before it has a chance to bind to the tissue.

[0206]Organic nitrates and nitrites act on almost all smooth muscle
structures, e.g., bronchial, biliary, gastrointestinal tract, uterine and
ureteral smooth muscles. Pain and other symptoms associated with
increased pressure can be transiently relieved. For example,
administration of a nitrate in a patient with T-tube drainage can reduce
biliary pressure and can induce rapid emptying of biliary contents into
the duodenum.

[0207]Nitrates, organic nitrates, nitroso compounds, and a variety of
other nitrogen oxide-containing compounds work by activating guanylate
cyclase and increasing the synthesis of guanosine 3',5'-monophosphate
(cyclic GMP) in smooth muscle and other tissues. These agents all lead to
the formation of nitric oxide (NO). Nitric oxide is a reactive free
radical that interacts with and activates guanylate cyclase. The
interaction of nitric oxide and guanylate cyclase stimulates cyclic-GMP
dependent protein kinase, which results in the phosphorylation of various
proteins in smooth muscle, which further results in de-phosphorylation of
the light chain of myosin, a protein thought to play an important role in
the contractile process in its phosphorylated form. Analogs of cyclic-GMP
can also relax vascular and bronchial smooth muscle (See: Goodman and
Gilman's "The Pharmacological Basis of Therapeutics," 9th edition,
Macmillan Publishing Co., 1996, pp 798-799 and 806-816).

[0209]Suitable doses of the nitrate vasodilator adjunctive agents vary due
to the wide variations in potency among the various nitrate vasodilators.
The dose is also dependant on the severity of the pain which must be
prevented or alleviated, the physical condition of the patient, the
relative severity and importance of adverse side effects, and other
factors within the judgment of the physician. In certain embodiments of
the present invention suitable doses of nitrate vasodilator adjunctive
agents may range from about 0.0001 to 120 mg/kg of body weight per day,
more preferably from about 0.01 to about 75 mg/kg and most preferably
from about 0.5 to about 30 mg/kg.

[0210]In certain embodiments of the present invention, oral doses of the
vasodilator adjunctive agents range from about 2.5 to about 300 mg/day of
nitrite, preferably from about 5 to about 160 mg/day.

[0211]In certain embodiments, a vasodilator and a vasoconstrictor can be
used as adjunctive therapy for capsaicinoid administration. For example,
the capsaicinoid can be administered with a vasodilator at the intended
site. To compliment the capsaicinoid therapy, a local anesthetic can be
administered at a distal site to provide a regional block at the site of
capsaicinoid administration. The vasoconstrictor can be administered with
the local anesthetic to prolong the duration of effect of the local
anesthetic.

[0212]In certain other embodiments there is provided a composition
comprising a capsaicinoid and one or more adjunctive agents disclosed
herein.

Breakthrough Pain

[0213]The term "breakthrough pain" means pain which the patient
experiences despite the fact that the patient is being or was
administered generally effective amounts of, e.g., capsaicin. In
conjunction with the use of the capsaicinoid formulations and methods
described herein, it is contemplated that it is nonetheless possible that
the patient will experience breakthrough pain. For the treatment of
breakthrough pain, the individual may be further administered an
effective amount of an analgesic in accordance with the treatment of pain
in such situations performed by those skilled in the art. The analgesic
may be any known to the person skilled in the art such as those selected
from the group comprising gold compounds such as sodium aurothiomalate;
non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen,
diclofenac, flurbiprofen, ibuprofen ketoprofen, ketorolac,
pharmaceutically acceptable salts thereof and the like; opioid analgesics
such as codeine, dextropropoxyphene, dihydrocodeine, morphine,
diamorphine, hydromorphone, hydrocodone, methadone, pethidine, oxycodone,
levorphanol, fentanyl and alfentanil, para-aminophenol derivatives such
as paracetamol, pharmaceutically acceptable salts thereof and the like;
and salicylates such as aspirin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Example I

Osteoarthritis of the Knee Safety Study

[0214]The following clinical study was carried out in order to evaluate
the safety, tolerability, systemic pharmacokinetics, and efficacy of
purified capsaicin administered by intra-articular infiltration together
with a local anesthetic administered by intra-articular infiltration in
subjects with osteoarthritis of the knee.

[0215]The primary objective of the study was to evaluate the safety and
tolerability of intra-articular capsaicin, when co-administered with
intra-articular local anesthetic, compared to placebo, in subjects with
end-stage osteoarthritis of the knee, already scheduled to receive knee
replacements.

[0216]Purified capsaicin was supplied in vials containing 5 mL of purified
capsaicin at a concentrations of 500 μg/mL. Study drug was stored at a
temperature between 15° C. and 25° C. Within four hours
prior to injection, vehicle was used to dilute the drug to final
concentrations of purified capsaicin, as follows:

[0217]Each vial was used for one infiltration administration only and
appropriately labeled. The supplier of the purified capsaicin was
FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The vials
were supplied in bulk to the study center with each vial labeled
according to the contents of the vial. The Pharmacist/Study Nurse, who
prepared the injection, maintained the investigational product in a
lockable cabinet at the required temperature, 15-25° C. The study
blind was maintained by the Pharmacist/Study Nurse.

[0218]Placebo vehicle for purified capsaicin was supplied in vials
containing 5 mL. Local anesthetic (Lignocaine 2%) was used for each
intra-articular infiltration.

[0219]The study was a single center, randomized, double blind, placebo
controlled, dose ranging Phase 1 study of three dose levels (10 μg,
100 μg, or 300 μg) of intra-articularly administered purified
capsaicin, when co-administered with intra-articular local anesthetic, in
subjects with osteoarthritis of the knee who were scheduled to undergo
total knee replacement. The doses of purified capsaicin used in this
trial were well below (>100 fold) doses known to be toxic to animals.
The study was designed to include 16 evaluation subjects. Sixteen
subjects were enrolled in the study; 12 were treated with ultra-purified
capsaicin (4 each with 10, 100, and 300 μg doses) and 4 were treated
with placebo vehicle. Sixteen subjects completed the study.

[0220]Patients were treated randomly and in double-blind fashion in four
treatment groups, with each group having a progressively longer interval
between the intra-articular administration of study medication and
subsequent total knee replacement (2, 4, 7, and 14 days). Four subjects,
1 in each of the 4 dose groups (placebo, 10 μg, 100 μg, and 300
μg of capsaicin), were enrolled in each treatment group. Gross and
microscopic pathology analysis was completed for each treatment group
before the next treatment group was treated.

[0221]Each subject had 3 study visits: a Screening Day (Day -7 to -1), the
Treatment Day (Day 0), and a Post-Treatment Day (scheduled for Day +2,
+4, +7, or +14). On the Treatment Day the subject was randomized,
pre-treatment evaluation was performed. The patients were brought into
the procedure room, and a VAS pain score was taken (0 mm--no pain, 100
mm--extreme pain). Once the patient had marked his or her pain on the
card, he/she was prepped for knee cannulation. Once the cannula was
placed, the patient received by intra-articular infiltration, 3 mg/kg
(maximum dose of 200 mg) of 2% lignocaine into the knee scheduled to be
replaced. This administration of local anesthetic was followed in 10
minutes by an intra-articular infiltration of placebo (vehicle) or 10
μg, 100 μg, or 300 μg of purified capsaicin diluted with vehicle
to a total volume of 5 mL.

[0222]VAS pain scores as well as verbal reports were taken immediately
following administration, as well as prior to knee replacement surgery.
No subjects discontinued from the study due to adverse events.

[0223]Immediately following instillation of capsaicin, some patients (0 of
4 receiving placebo, 0 of 4 receiving 10 μg capsaicin, 1 of 4
receiving 100 μg capsaicin, and 4 of 4 receiving 300 μg capsaicin)
reported transient burning pain representative of capsaicin injection
(onset within a few seconds to minutes and lasting less than one hour).
Pain was mild but for some patients, the investigator chose to place ice
packs on the treated knee until the pain resolved. In particular, the
subject in the 100 μg dose group and 2 of the subjects in the 300
μg dose group had burning post-administration (hyper) algesic pain
alone; two subjects in the 300 μg dose group had burning pain in
conjunction with other types of post-administration (hyper) algesic pain
(1 subject had burning and stinging pain and the second subject had
burning and toothache-like pain). All of the episodes of
post-administration (hyper) algesia began immediately (within 5 minutes)
after administration. All of these painful episodes were brief: the
duration of this pain was 9 minutes for the subject in the 100 μg dose
group, and 17, 25, 25, and 42 minutes for the subjects in the 300 μg
dose group. The 4 subjects in the 300 μg dose group and 1 subject in
the 100 μg dose group required intervention for their post-injection
(hyper) algesia. For all but 1 of these 5 subjects, the only intervention
was ice packs. One subject in the 300 μg dose group was treated with
paracetamol; no subjects were treated with intravenous morphine or
granisetron for post-administration (hyper) algesia. Most of the
concomitant medications used in the study were medications taken prior to
the study that continued to be taken during the study. The only
concomitant non-drug treatments during the study were the ice packs used
in the 5 subjects with post-administration (hyper) algesia.

[0224]On the Post-Treatment Day, study evaluation was performed followed
by the scheduled knee replacement, with intra-operative bone and soft
tissue biopsies performed for subsequent examination. For overall
efficacy analysis, we chose to exclude the patients who had surgery two
days following administration since analgesia from remaining lignocaine
or residual pain from the actual procedure (large volume infiltration)
and lysing c-fiber endings could not be excluded (In normal volunteers, a
mild "aching" pain is sometimes observed for up to two days following
capsaicin administration). This therefore left the 3 placebo and 9 active
patients from the 4 day, 7 day, and 14 day cohorts. Examination of the
VAS scores prior to drug/placebo administration and the day of surgery
(prior to surgery) showed that pain scores were not reduced in the
placebo group (VAS decreased by only 7±30%), but was reduced in the
capsaicin group (VAS reduced by 62±14%). The changes in VAS score are
reported graphically as shown in FIG. 1. The plasma concentration over
time of the three dosage ranges of capsaicin are shown in FIG. 2.

[0225]Ten-mL blood samples for subsequent assay of plasma ultra-purified
capsaicin concentrations were collected prior to study medication
administration, at 30 minutes, 1, 2, and 4 hours after study medication
injection, and immediately prior to the first administration of
pre-operative medications on the Post Treatment Day. The pharmacokinetic
parameters of Cmax, Tmax, AUC(0-tlast) and t1/2 were evaluated.

[0226]In the 10 μg dose group, purified capsaicin plasma concentrations
were measurable at only 0, 1, or 2 time points; therefore, no
pharmacokinetic parameters could be estimated for any subject in this
dose group. For the 3 subjects in each of the 100 μg, and

300 μg dose groups for which pharmacokinetic parameters could be
estimated, the magnitude of the Cmax and AUC(0-tlast) values was
similar in the 2 dose groups. Tmax values were 0.5 hr in all subjects for
which they could be estimated. Terminal exponential half-lives were
similarly brief in all subjects in both the 100 μg and 300 μg dose
groups.

[0227]The AUC(0-tlast) values for the subjects in the 100 μg dose
group (366.10, 75.19, and 511.21 pg*hr/mL) were similar in magnitude to
the values for the 300 μg dose group (449.01, 220.42, and 498.83
pg*hr/mL). Similarly, the Cmax values in the 100 μg dose group
(292.06, 79.94, and 538.32 pg/mL) were similar in magnitude to the values
in the 300 μg dose group (207.62, 251.42, and 499.88 pg/mL). Tmax
was 0.5 hours in all 6 subjects. The terminal exponential half lives were
brief in all subjects, with values of 0.1498, 1.1488, and 0.1014 hr in
the 100 μg dose group and values of 0.3268, 0.2298, and 0.1663 in the
300 μg dose group.

[0228]The pharmacokinetic conclusions are necessarily limited, because the
number of timepoints at which plasma concentrations of purified capsaicin
was measurable was so limited in these study subjects. However, there was
some evidence for a pharmacokinetic dose response over the 10 μg to
300 μg dose range in that the purified capsaicin plasma concentrations
in the 10 μg dose group were clearly lower than in either the 100
μg or the 300 μg dose groups. However, there was little evidence
for a pharmacokinetic dose response over the 100-300 μg dose range.

[0229]Purified capsaicin was well tolerated at all dose levels. There was
low leakage of study drug from the joint space and gross and microscopic
pathology was normal. There were no treatment related signs of erythema,
edema, or hemorrhage at the site of injection, and no treatment related
effects on soft tissue, cartilage, or bone upon histopathological
examination. No treatment related systemic side effects were seen, and
there were no treatment related effects on laboratory safety parameters
or vital signs. There was no discernable effect on proprioception at the
injected knee in any dose group at any time point.

[0230]There was a clear dose response for the incidence of post injection
hyperalgesia. This symptom occurred in 4 subjects in the 300 μg dose
group, 1 subject in the 100 μg dose group, and no subjects in the 10
μg dose group or placebo. In all but one case, the hyperalgesia was
described as a burning sensation, which developed within five minutes of
injection and lasted on average less than thirty minutes. In all cases
where intervention was required, the hyperalgesia was easily and
effectively controlled by the application of ice packs to the knee.

[0231]Subjects were asked to rank their level of pain on a visual analogue
scale (VAS), anchored by "no pain" on the left and "extreme pain" on the
right, prior to receiving the intra-articular dose of purified capsaicin
and local anesthetic and then again just prior to administration of
preoperative medications on the day of knee replacement surgery. No clear
treatment related indication of efficacy was seen at any of the dose
levels (10 μg, 100 μg, and 300 μg) of purified capsaicin.

[0232]Since intra-articular infiltration of local anesthetic followed by
intra-articular infiltration of capsaicin was generally well-tolerated,
and the median decreases from baseline to the pre-operative time point in
the VAS for pain at the target knee in all 3 capsaicin dose groups were
all substantially greater that the median change from baseline in the
placebo group, the risk to benefit ratio of this treatment strategy
appears favorable. Further studies of this treatment in larger numbers of
subjects with osteoarthritis appear warranted.

Example II

Osteoarthritis of the Knee Efficacy Study

[0233]The following clinical study evaluates the efficacy of purified
capsaicin administered by intra-articular infiltration together with a
local anesthetic injected by intra-articular infiltration in subjects
with osteoarthritis of the knee.

[0234]The primary objective of the study is to evaluate the efficacy of
intra-articular capsaicin, when co-administered with intra-articular
local anesthetic, compared to placebo, in subjects with end-stage
osteoarthritis of the knee, already scheduled to receive knee
replacements (21 and 42 days after injection of study medication).

[0235]Purified capsaicin is supplied in vials containing 5 mL of purified
capsaicin at a concentrations of 500 μg/mL. Study drug was stored at a
temperature between 15° C. and 25° C. Within four hours
prior to injection, vehicle is used to dilute the drug to final
concentrations of purified capsaicin, as follows:

[0236]Each vial is used for one infiltration administration only and
appropriately labeled. The supplier of the purified capsaicin is
FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The vials are
supplied in bulk to the study center with each vial labeled according to
the contents of the vial. The Pharmacist/Study Nurse, who prepares the
injection, maintains the investigational product in a lockable cabinet at
the required temperature, 15-25° C. The study blind is maintained
by the Pharmacist/Study Nurse.

[0237]Placebo vehicle for purified capsaicin is supplied in vials
containing 5 mL. Local anesthetic (Lignocaine 2%) is used for each
subacromial bursa infiltration.

[0238]The study is a single center, randomized, double blind, placebo
controlled, dose ranging Phase 2 study of capsaicin (1000 μg)
administered by intra-articular infiltration, when co-administered with
intra-articular local anesthetic, in subjects with osteoarthritis of the
knee who are scheduled to undergo total knee replacement from three to
six weeks post study drug administration, wherein the primary endpoint is
pain reduction at three weeks following study drug administration.

[0239]The study is designed to include 12 evaluation subjects (Patients
suffering a defined pain: >40 mm on VAS). Six (6) subjects will be
treated with capsaicin 1000 μg and 6 subjects will be treated with
placebo vehicle. Patients are treated randomly and in double-blind
fashion. Gross and microscopic pathology analysis are completed for each
treatment group. Each subject has 3 study visits: a Screening Day (Day -7
to -1), the Treatment Day (Day 0), and a Post-Treatment Day (scheduled
for Day +2, +4, +7, or +14). On the Treatment Day the subject is
randomized, pre-treatment evaluation is performed. The patient is brought
into the procedure room, and a VAS pain score is taken (0 mm--no pain,
100 mm--extreme pain). Once the patient marks his or her pain on the
card, he/she is prepped for knee cannulation. Once the cannula is placed,
the patient receives, by intra-articular infiltration, 3 mg/kg (maximum
dose of 200 mg) of 2% lignocaine into the knee scheduled to be replaced.
This infiltration of local anesthetic is followed in 10 minutes by an
intra-articular infiltration of placebo (vehicle) or 1000 μg of
purified capsaicin diluted with vehicle to a total volume of 5 mL.

[0240]VAS pain scores as well as verbal reports are taken immediately
following administration, as well as prior to knee replacement surgery.
On the Post-Treatment Day, a study evaluation is performed followed by
the scheduled knee replacement, with intra-operative bone and soft tissue
biopsies performed for subsequent examination. For overall efficacy
analysis, patients having surgery two days following infiltration are
excluded since analgesia from remaining lignocaine or residual pain from
the actual procedure (large volume injection) and lysing c-fiber endings
is not capable of being excluded.

[0242]The following study was carried out in order to evaluate the safety,
tolerability, systemic pharmacokinetics, and efficacy of intra-operative
(infiltration) capsaicin when co-administered with a local anesthetic in
patients scheduled to undergo transpositional osteotomy (bunionectomy).

[0243]The primary objective of the study was to evaluate the safety and
tolerability of capsaicin, when co-administered by intra-articular
infiltration with a local anesthetic, compared to placebo, in subjects
with hallux valgus deformity, already scheduled to undergo
transpositional osteotomy (bunionectomy). The secondary objective of the
study was to evaluate the safety, tolerability and systemic
pharmacokinetics of purified capsaicin following intra-operative
administration. The primary efficacy endpoint was the proportion of
subjects in each treatment group requiring opioid analgesia in the first
24 hours post-operatively. The proportions were compared amongst
treatment groups using the Cochran-Haenszel test. Secondary efficacy end
points included: i) proportion of subjects in each treatment group
requiring opioid analgesia in the first 36 hour period post-operatively
(Similarly, the proportions were compared amongst treatment groups using
the Cochran-Haenszel test); ii) proportion of subjects in each treatment
group requiring opioid analgesia in the 10 day period post-operatively
(Similarly, the proportions were compared amongst treatment groups using
the Cochran-Haenszel test); iii) time to first usage of opioid analgesia
in each treatment group (a survival analysis approach will be used: the
product-limit (Kaplan-Meier) method will be applied to time to first
usage of opioid analgesia. The median time to first usage of opioid
analgesia will be estimated in both treatment groups. Pairwise
comparisons will be performed to test for equality of the survival curves
between the 2 treatment groups using both the log-rank and the Wilcoxon
test); iv) total usage of analgesia in each treatment group (the total
usage of analgesia will be compared by an analysis of variance with
treatment and center as independent variables. A pairwise comparison will
be performed between the treatment groups); and v) VAS assessment of pain
at the site of operation in each treatment group (The VAS score at each
time point will be compared by an analysis of variance with treatment and
center as independent variables. A pairwise comparison will be performed
between the treatment groups). Safety endpoints included: i) laboratory
safety parameters; ii) adverse events; and iii) purified capsaicin blood
levels. The efficacy analysis was performed on the data obtained ten days
postoperatively. The safety analysis was performed based on the safety
data for the entire study, including the 6 week and 12 week follow-up
periods. The blind was broken at the time the efficacy analysis was
performed. However, the individual treatment assignment was available to
the statistical analysis group only. All other personnel involved in the
study, including the Investigator, study monitor and proprietary staff,
remained blinded until the entire study was completed.

[0244]Purified capsaicin was supplied in vials containing 5 mL of purified
capsaicin at a concentrations of 500 μg/mL. Study drug was stored at a
temperature between 15° C. and 25° C. Within four hours
prior to injection, vehicle was used to dilute the drug to final
concentrations of purified capsaicin, as follows:

[0245]Each vial was used for one infiltration administration only and
appropriately labeled. The supplier of the purified capsaicin was
FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The vials
were supplied in bulk to the study center with each vial labeled
according to the contents of the vial. The Pharmacist/Study Nurse, who
prepared the injection, maintained the investigational product in a
lockable cabinet at the required temperature, 15-25° C. The study
blind was maintained by the Pharmacist/Study Nurse.

[0246]Placebo vehicle for purified capsaicin was supplied in vials
containing 5 mL. Local anesthetic (Lignocaine 2%) was used for each
infiltration.

[0247]The study was a single center, randomized, double blind, placebo
controlled, Phase II study of the safety and efficacy of intra-operative
capsaicin, when co-administered with local anaesthetic, in subjects
undergoing transpositional first metatarsal osteotomy and fixation for
the correction of hallux valgus deformity. The dose of capsaicin used in
the trial was 1000 μg.

[0248]The study was designed to include 40 evaluation subjects. Twenty
(20) randomized to the capsaicin treatment group and twenty (20) to the
placebo control group. Each subject had six (6) study visits: a Screening
Day (Day -28 to -1), an Operation Day (Day 0), and four (4) Follow-up
visits (scheduled for Days 3, 10 and weeks 6 and 12).

[0249]On Operation Day (Day 0) the following was performed: a)
Pre-operation: Prior to the initiation of an ankle block,
inclusion/exclusion criteria assessment was performed. Eligible subjects
were randomized, pre-treatment evaluation was performed, which included
laboratory safety assessments, measurement of vital signs, VAS assessment
of pain at the target Hallux valgus, blood sample measurement for
purified capsaicin concentration, and review of concomitant medications;
b) Operation: An ankle block [lidocaine 0.5% (up to a total of 20 ml)]
was initiated by the investigator to provide surgical anesthesia, and
then a transpositional osteotomy of the first metatarsal +/- an Akin
osteotomy of the proximal phalanx in accordance with normal practices and
procedures was performed. Immediately prior to wound closure, the
Investigator slowly dripped the study medication (4 mL) from a syringe
into the wound, ensuring even tissue exposure. The wound was then be
closed according to normal practices and procedures.

Post-Operation:

[0250]In the 24 hours following administration of study medication, vital
signs (supine pulse rate and blood pressure) were recorded at 1, 2, 4 and
24 hours post administration. VAS assessment of pain at the operation
site was performed at 1, 4, 8, 12 and 24 hours post administration. In
those instances where VAS measurements coincide with blood sampling
procedures, the VAS assessment was performed first. Blood samples for
measurement of capsaicin concentration were obtained at 1, 2, and 4 hours
post administration. The quantity of each blood sample was 10 mL.
Laboratory safety assessments, e.g., haematology, biochemistry,
urinalysis were performed at 24 hours post administration. Adverse events
were spontaneously reported by the subject and recorded. Rescue analgesia
medication was provided to the subject if required (initially diclofenac
50 mg, repeated at 8 hourly intervals if necessary). When diclofenac was
judged by the Investigator to provide inadequate pain relief then the
subject was provided with alfentanil 1 mg, repeated at 6 hourly
intervals, if necessary. After discharge from the hospital, alfentanil
was substituted with co-codamol 30/500 (codeine phosphate 30
mg+paracetamol 500 mg), repeated at 4 hourly intervals when necessary.
Any usage of rescue medication or concomitant medication was recorded in
the subject's CRF. At 24 hours post administration of study medication,
the subject was discharged from the clinic.

Follow Up:

[0251]Follow-up (days 1-10): Upon discharge from the clinic, the subject
was provided with a diary card for Days 1-10, and asked to record: VAS
assessment of pain at the operation site, performed each morning; time
and amount of any rescue medication taken by the subject (at any time);
usage of concomitant medications (at any time); adverse events
experienced by the subject (at any time). Each subject was also be asked
to return to the clinic on Day 3 and on Day 10 post-operation. At these
clinic visits the Investigator examined the subject's diary card and
resolved any unclear or inconsistent entries. Data from the diary card
was transcribed to the subject's CRF. The site of the operation was
inspected by the Investigator to confirm that normal wound healing took
place.

[0252]Follow Up (Week 6): The subject was asked to return to the clinic at
6 weeks post operation. The site of the operation was inspected by the
Investigator to confirm that normal wound healing is took place. The
subject was questioned about any adverse events he/she experienced since
the last clinic visit, and any usage of concomitant medication.

[0253]Follow Up (Week 12): The subject was asked to return to the clinic
at 12 weeks post operation. The site of the operation was inspected by
the Investigator to confirm that normal wound healing is took place. The
subject was questioned about any adverse events he/she may experienced
since the last clinic visit, and any usage of concomitant medication. The
Investigator discharge the subject from the study.

[0254]The results of the bunionectomy study proved that capsaicin
administered at a dose of 1000 μg into the wound prior to wound
closure reduced both pain score as well as the use of rescue as shown in
FIGS. 3 and 4. Reduction in rescue was almost always associated with
maintenance of VAS score, i.e., the new drug simply substitutes for the
old drug (See; Table 4 below):

[0256]The primary objective of the study is to determine the amount of
opioid consumption and postoperative pain scores following median
sternotomy for patients receiving purified capsaicin by infiltration
and/or injection. Eligible subjects are patients undergoing cardiac,
pulmonary, or mediastinal surgery for any indication between the ages of
20-70 years. The operation is performed under general anesthesia and are
closely observed in a post-anesthesia care unit as per the practice of
the institution. The study drug will be administered to the sternal
edges, muscles (e.g., muscle edges), bone (e.g., bone edges), and
tissues. All patients receive standard of care opioid on demand for
treatment of pain when transferred to the ward. The dose of capsaicin is
administered to the sternal edges, the muscle, the tissues and/or bone.

[0257]Pain is assessed utilizing VAS 100 mm scale--baseline, every 60
minutes beginning when the patient first is placed in a bedside chair (or
ambulated) for 24 hours and then every 4 hours while awake until
discharge from the hospital. Patient diaries will be used following
discharge for a two-week period.

[0258]The primary study endpoint is the time to first request of
postoperative opioid. The amount of opioid rescue used is recorded every
24 hours for the first 2 weeks, patients will complete an opioid-related
symptom distress (SDS) questionnaire.

Example V

Laparoscopic Cholecystectomy Study

[0259]The primary objective of this study is to evaluate the amount of
opioid consumption and postoperative pain scores following laparoscopic
cholecystectomy in patients administered purified capsaicin by
infiltration and/or injection. Study subjects will receive a dose of
purified capsaicin in proximity to the surgical site.

[0260]This study includes 40 patients (20 randomized to receive capsaicin
study drug and 20 randomized to receive placebo study drug) between the
ages of 20-60 years old with symptomatic gallstones. The operation is
performed under general anesthesia and the subject is closely observed in
a post-anesthesia care unit for up to 24 hours and remains in the
hospital (typically for 1 to 5 days). All patients receive standard of
care opioid on demand for treatment of pain before discharge, and opioid
(to be determined) post discharge. Pain is assessed utilizing VAS 100 mm
scale--baseline, every 30 minutes till the 2nd postoperative hour then
every 4 hours the following 12 hours, an at 24 hours and at days 2, 3, 4,
5, 6 and 7. Patient diaries are used following discharge. Study subject
will receive a dose of purified capsaicin 1000-3000 μg divided over
the 4 part wounds-infiltrated along the cut muscle edges.

[0261]The primary study endpoint is the time to first request of
postoperative analgesia The amount of opioid rescue is every 24 hours for
first 3 days, patients complete an opioid-related symptom distress (SDS)
questionnaire.

Example VI

Knee Replacement Study

[0262]The primary objective of the study evaluates the amount of opioid
consumption and postoperative pain scores following knee replacement
surgery for patients receiving administration of purified capsaicin by
infiltration.

[0264]The knee replacement operation is performed under general anesthesia
and is closely observed in a post-anesthesia care unit as per the
practice of the institution. All patients receive standard of care opioid
on demand for treatment of pain once transferred to the ward. The volume
of capsaicin administered into the wound opening during closure ranges
from about 5 ml to about 10 ml.

[0265]Pain is assessed utilizing VAS 190 mm scale--baseline, every 60
minutes beginning when the patient first is placed on mechanical
flexion/extension for 24 hours and then every 4 hours while awake until
discharge from the hospital. Patient diaries are used following discharge
for a two-week period.

Example VII

Mastectomy Study

[0266]Mastectomy results in significant pain and requires substantial
doses of opioids postoperatively. Analgesic techniques that provide good
pain control while minimizing opioid side effects are thus highly
desirable. The primary objective of the study is to determine the amount
of opioid consumption and postoperative pain scores following mastectomy
for patients receiving capsaicin.

[0267]The study includes 80 patients (20 patients are randomized to
receive placebo, 20 randomized to receive capsaicin 300 μg, 20
randomized to receive capsaicin 1000 μg, and 20 randomized to receive
capsaicin 2000 μg). Eligible patients include patients undergoing
mastectomy between the ages of 20-70 years old. The operation is
performed under general anesthesia and is closely observed in a
post-anesthesia care unit as per the practice of the institution. All
patients receive standard of care opioid on demand for treatment of pain
once transferred to the ward.

[0268]The dose of study drug is administered by infiltration in a volume
from about 5 ml to about 10 ml within the wound cavity during closure.

[0269]Pain is assessed utilizing VAS 100 mm scale--baseline, every 60
minutes beginning when the patient first is placed on mechanical
flexion/extension for 24 hours and then every 4 hours while awake until
discharge from the hospital. Patient diaries are used following discharge
for a two-week period.

[0270]The primary endpoint is time to first request of postoperative
opioid. Opioid rescue occurs every 24 hours for the first 2 weeks,
patients complete an opioid-related symptom distress (SDS) questionnaire.

Example VIII

[0271](i) Examples I to VII are repeated and ibuprofen is administered
orally in an amount of 10/mg/kg before, during or after the
administration of the capsaicinoid in order to decrease the pain and
inflammation at the site of capsaicinoid administration.

[0272](ii) Examples I to VII are repeated and carbamazepine is
administered orally in an amount of 800 mg/day, before, during or after
the administration of the capsaicinoid in order to decrease propagation
and/or generate action potentials.

[0273](iii) Examples I to VII are repeated and amitriptyline is
administered orally in an amount of 100 mg/day either before, during or
after the administration of the capsaicinoid in order to diffuse the
capsaicinoid throughout the area.

[0274](iv) Examples I to VII are repeated and epinephrine is administered
parenterally at the site of action either before, during or after the
administration of the capsaicinoid restrict the capsaicinoid at the area.

[0275](v) Examples I to VII are repeated and isosorbide dinitrite is
administered by injection at the site of administration of the
capsaicinoid either before, during or after the administration of the
capsaicinoid in order to diffuse the capsaicinoid throughout the area.

[0276]The invention has been described in an illustrative manner, and it
is to be understood that the particular embodiments of the capsaicinoid
formulations and methods of treatment described herein are intended to be
descriptive rather than limiting. Many modifications and variations of
the methodologies and formulations disclosed herein are possible in light
of the above teachings, and such obvious modifications are deemed to be
encompassed within the scope of the appended claims.